Cyclopropyl amine derivatives

ABSTRACT

Compounds of formula (I) 
                         
are useful in treating conditions or disorders prevented by or ameliorated by histamine-3 receptor ligands. Also disclosed are pharmaceutical compositions comprising the histamine-3 receptor ligands, methods for using such compounds and compositions, and a process for preparing compounds within the scope of formula (I).

This application claims the benefit of U.S. Patent Application No.60/815,934, filed Jun. 23, 2006, which is hereby incorporated byreference.

BACKGROUND OF THE INVENTION

1. Technical Field

The invention relates to cyclopropyl amine compounds, compositionscomprising such compounds, methods for making the compounds, and methodsof treating conditions and disorders using such compounds andcompositions.

2. Description of Related Technology

Histamine is a well-known modulator of neuronal activity. At least fourtypes of histamine receptors have been reported in the literature,typically referred to as histamines-1, histamine-2, histamine-3, andhistamine-4. The class of histamine receptor known as histamine-3receptors is believed to play a role in neurotransmission in the centralnervous system.

The histamine-3 (H₃) receptor was first characterized pharmacologicallyon histaminergic nerve terminals (Nature, 302:832-837 (1983)), where itregulates the release of neurotransmitters in both the central nervoussystem and peripheral organs, particularly the lungs, cardiovascularsystem and gastrointestinal tract. H₃ receptors are thought to belocated presynaptically on histaminergic nerve endings, and also onneurons possessing other activity, such as adrenergic, cholinergic,serotoninergic, and dopaminergic activity. The existence of H₃ receptorshas been confirmed by the development of selective H₃ receptor agonistsand antagonists ((Nature, 327:117-123 (1987); Leurs and Timmerman, ed.“The History of H₃ Receptor: a Target for New Drugs,” Elsevier (1998)).

The activity at the H₃ receptors can be modified or regulated by theadministration of H₃ receptor ligands. The ligands can demonstrateantagonist, inverse agonist, agonist, or partial agonist activity. Forexample, H₃ receptors have been linked to conditions and disordersrelated to memory and cognition processes, neurological processes,cardiovascular function, and regulation of blood sugar, among othersystemic activities. Although various classes of compounds demonstratingH₃ receptor-modulating activity exist, it would be beneficial to provideadditional compounds demonstrating activity at the H₃ receptors that canbe incorporated into pharmaceutical compositions useful for therapeuticmethods.

SUMMARY OF THE INVENTION

The invention is directed to cyclopropyl amines and, more particularly,bicyclic- and tricyclic-substituted cyclopropyl amine derivatives.Accordingly, one aspect of the invention relates to compounds of formula(I).

or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof,wherein:

one of R₁ and R₂ is a group of the formula -L₂-R_(6a)-L₃-R_(6b);

the other of R₁ and R₂ is selected from hydrogen, alkyl, alkoxy,halogen, cyano, and thioalkoxy;

R₃, R_(3a), and R_(3b) are each independently selected from the groupconsisting of hydrogen, alkyl, trifluoroalkyl, trifluoroalkoxy, alkoxy,halogen, cyano, and thioalkoxy

R₄ and R₅ are each independently selected from alkyl, fluoroalkyl,hydroxyalkyl, alkoxyalkyl, and cycloalkyl, or R₄ and R₅ taken togetherwith the nitrogen atom to which each is attached form a non-aromaticring of the formula

R₇, R₈, R₉, and R₁₀ at each occurrence are each independently selectedfrom hydrogen, hydroxyalkyl, fluoroalkyl, cycloalkyl, and alkyl;

R₁₁, R₁₂, R₁₃, and R₁₄ are each independently selected from hydrogen,hydroxyalkyl, alkyl, and fluoroalkyl;

R_(6a) is selected from a 5- to 6-membered heteroaryl ring, cyanophenyl,an 8- to 12-membered bicyclic heteroaryl ring, and a 4- to 12-memberedheterocyclic ring;

R_(6b) is selected from hydrogen, a 5- to 6-membered heteroaryl ring, anaryl ring, an 8- to 12-membered bicyclic heteroaryl ring, and a 4- to12-membered heterocyclic ring;

Q is selected from O and S;

L is —[C(R₁₆)(R₁₇)]_(k);

L₂ is selected from a bond, alkylene, —O—, —C(═O)—, —S—, —NH—,—N(R₁₆)C(═O)—, —C(═O)N(R₁₆), and —N(alkyl)-;

L₃ is selected from a bond, alkylene, —O—, —C(═O)—, —S—, —N(R₁₆)C(═O)—,—C(═O)N(R₁₆), and —N(R₁₅)—;

R₁₅ is selected from hydrogen, alkyl, acyl, alkoxycarbonyl, amido, andformyl;

R₁₆ and R₁₇ at each occurrence are independently selected from hydrogenand alkyl;

R_(x) and R_(y) at each occurrence are independently selected fromhydrogen, hydroxy, alkyl, alkoxy, alkylamino, fluoro, and dialkylamino;

k is 1, 2, or 3, and

m is an integer from 1 to 5.

Another aspect of the invention relates to pharmaceutical compositionscomprising compounds of the invention. Such compositions can beadministered in accordance with a method of the invention, typically aspart of a therapeutic regimen for treatment or prevention of conditionsand disorders related to H₃ receptor activity.

Yet another aspect of the invention relates to a method of selectivelymodulating H₃ receptor activity. The method is useful for treating, orpreventing conditions and disorders related to H₃ receptor modulation inmammals. More particularly, the method is useful for treating orpreventing conditions and disorders related to memory and cognitionprocesses, neurological processes, cardiovascular function, and bodyweight. Accordingly, the compounds and compositions of the invention areuseful as a medicament for treating or preventing H₃ receptor modulateddiseases.

Processes for making compounds of the invention also are contemplated.

The compounds, compositions comprising the compounds, methods for makingthe compounds, and methods for treating or preventing conditions anddisorders by administering the compounds are further described herein.

DETAILED DESCRIPTION OF THE INVENTION Definition of Terms

Certain terms as used in the specification are intended to refer to thefollowing definitions, as detailed below.

The term “acyl” as used herein means an alkyl group, as defined herein,appended to the parent molecular moiety through a carbonyl group, asdefined herein. Representative examples of acyl include, but are notlimited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl,and 1-oxopentyl.

The term “acyloxy” as used herein means an acyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of acyloxy include, but are not limited to,acetyloxy, propionyloxy, and isobutyryloxy.

The term “alkenyl” as used herein means a straight or branched chainhydrocarbon containing from 2 to 10 carbons, and preferably 2, 3, 4, 5,or 6 carbons, and containing at least one carbon-carbon double bondformed by the removal of two hydrogens. Representative examples ofalkenyl include, but are not limited to, ethenyl, 2-propenyl,2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl,2-methyl-1-heptenyl, and 3-decenyl.

The term “alkoxy” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkoxyalkoxy” as used herein means an alkoxy group, as definedherein, appended to the parent molecular moiety through another alkoxygroup, as defined herein, Representative examples of alkoxyalkoxyinclude, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy,2-methoxyethoxy, and methoxymethoxy.

The term “alkoxyalkyl” as used herein means an alkoxy group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of alkoxyalkyl include, butare not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl,and methoxymethyl.

The term “alkoxycarbonyl” as used herein means an alkoxy group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, and tert-butoxycarbonyl.

The term “alkoxyimino” as used herein means an alkoxy group, as definedherein, appended to the parent molecular moiety through an imino group,as defined herein. Representative examples of alkoxyimino include, butare not limited to, ethoxy(imino)methyl and methoxy(imino)methyl.

The term “alkoxysulfonyl” as used herein means an alkoxy group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofalkoxysulfonyl include, but are not limited to, methoxysulfonyl,ethoxysulfonyl, and propoxysulfonyl.

The term “alkyl” as used herein means a straight or branched chainhydrocarbon containing from 1 to 10 carbon atoms, and preferably 1, 2,3, 4, 5, or 6 carbons. Representative examples of alkyl include, but arenot limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl,3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl,n-octyl, n-nonyl, and n-decyl.

The term “alkylamino” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through a NH group,Representative examples of alkylamino include, but are not limited to,methylamino, ethylamino, isopropylamino, and butylamino.

The term “alkylcarbonyl” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through a carbonylgroup, as defined herein. Representative examples of alkylcarbonylinclude, but are not limited to, methylcarbonyl, ethylcarbonyl,isopropylcarbonyl, n-propylcarbonyl, and the like.

The term “alkylene” means a divalent group derived from a straight orbranched chain hydrocarbon of from 1 to 10 carbon atoms, Representativeexamples of alkylene include, but are not limited to, —CH₂—, —CH(CH₃)—,—C(CH₃)₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and —CH₂CH(CH₃)CH₂—.

The term “alkylsulfonyl” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through a sulfonylgroup, as defined herein. Representative examples of alkylsulfonylinclude, but are not limited to, methylsulfonyl and ethylsulfonyl.

The term “alkynyl” as used herein means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms, and preferably2, 3, 4, or 5 carbons, and containing at least one carbon-carbon triplebond. Representative examples of alkynyl include, but are not limitedto, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and1-butynyl.

The term “amido” as used herein means an amino, alkylamino, ordialkylamino group appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples of amidoinclude, but are not limited to, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, and ethylmethylaminocarbonyl.

The term “amino” as used herein means a —NH₂ group.

The term “aryl” as used herein means a monocyclic hydrocarbon aromaticring system. Representative examples of aryl include, but are notlimited to, phenyl.

The aryl groups of this invention are substituted with 0, 1, 2, 3, 4, or5 substituents independently selected from acyl, acyloxy, alkenyl,alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino,alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, amido,carboxy, cyano, cycloalkylcarbonyl, formyl, haloalkoxy, haloalkyl,halogen, hydroxy, hydroxyalkyl, mercapto, nitro, thioalkoxy,NR_(A)R_(B), and (NR_(A)R_(B))sulfonyl.

The term “arylalkyl” as used herein means an aryl group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of arylalkyl include, but arenot limited to, benzyl, 2-phenylethyl and 3-phenylpropyl.

The term “carbonyl” as used herein means a —C(═O)— group.

The term “carboxy” as used herein means a —CO₂H group, which may beprotected as an ester group —CO₂-alkyl.

The term “cyano” as used herein means a —CN group.

The term “cyanophenyl” as used herein means a —CN group appended to theparent molecular moiety through a phenyl group, including, but notlimited to, 4-cyanophenyl, 3-cyanophenyl, and 2-cyanophenyl.

The term “cycloalkyl” as used herein means a saturated cyclichydrocarbon group containing from 3 to 8 carbons. Examples of cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,and cyclooctyl.

The cycloalkyl groups of the invention are substituted with 0, 1, 2, 3,or 4 substituents selected from acyl, acyloxy, alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkyl, alkynyl,amido, carboxy, cyano, ethylenedioxy, formyl, haloalkoxy, haloalkyl,halogen, hydroxy, hydroxyalkyl, methylenedioxy, oxo, thioalkoxy, and—NR_(A)R_(B).

The term “cycloalkylcarbonyl” as used herein means a cycloalkyl group,as defined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein, Representative examples ofcycloalkylcarbonyl include, but are not limited to, cyclopropylcarbonyl,cyclopentylcarbonyl, cyclohexylcarbonyl, and cycloheptylcarbonyl.

The term “dialkylamino” as used herein means two independent alkylgroups, as defined herein, appended to the parent molecular moietythrough a nitrogen atom, Representative examples of dialkylaminoinclude, but are not limited to, dimethylamino, diethylamino,ethylmethylamino, and butylmethylamino.

The term “fluoro” as used herein means —F.

The term “fluoroalkoxy” as used herein means at least one fluoroalkylgroup, as defined herein, appended to the parent molecular moietythrough an oxygen group, as defined herein. Representative examples offluoroalkyl include, but are not limited to, trifluoromethoxy (CF₃O),and difluoromethoxy (CHF₂O).

The term “fluoroalkyl” as used herein means at least one fluoro group,as defined herein, appended to the parent molecular moiety through analkyl group, as defined herein. Representative examples of fluoroalkylinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, pentafluoroethyl, and 2,2,2-trifluoroethyl.

The term “formyl” as used herein means a C(O)H group.

The term “halo” or “halogen” as used herein means Cl, Br, I, or F.

The term “haloalkoxy” as used herein means at least one halogen, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein. Representative examples of haloalkoxyinclude, but are not limited to, 2-fluoroethoxy, trifluoromethoxy, andpentafluoroethoxy.

The term “haloalkyl” as used herein means at least one halogen, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of haloalkyl include,but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl,pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term “heteroaryl”, as used herein, refers to an aromatic ringcontaining one or more heteroatoms independently selected from nitrogen,oxygen, or sulfur, or a tautomer thereof. Such rings can be monocyclicor bicyclic as further described herein. Heteroaryl rings are connectedto the parent molecular moiety, or to L₂ or L₃, wherein L₂ and L₃ aredefined in formula (I), through a carbon or nitrogen atom.

The terms “monocyclic heteroaryl” or “5- or 6-membered heteroaryl ring”,as used herein, refer to 5- or 6-membered aromatic rings containing 1,2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or a tautomer thereof. Examples of such rings include, but arenot limited to, a ring wherein one carbon is replaced with an O or Satom, one, two, or three N atoms arranged in a suitable manner toprovide an aromatic ring; or a ring wherein two carbon atoms in the ringare replaced with one O or S atom and one N atom. Such rings caninclude, but are not limited to, a six-membered aromatic ring whereinone to four of the ring carbon atoms are replaced by nitrogen atoms,five-membered rings containing a sulfur, oxygen, or nitrogen in thering, five membered rings containing one to four nitrogen atoms, andfive membered rings containing an oxygen or sulfur and one to threenitrogen atoms, Representative examples of 5- to 6-membered heteroarylrings include, but are not limited to, furyl, imidazolyl, isoxazolyl,isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolyl, tetrazolyl, [1,2,3]thiadiazolyl,[1,2,3]oxadiazolyl, thiazolyl, thienyl, [1,2,3]triazinyl,[1,2,4]triazinyl, [1,3,5]triazinyl, [1,2,3]triazolyl, and[1,2,4]triazolyl.

The term “bicyclic heteroaryl” or “8- to 12-membered bicyclic heteroarylring”, as used herein, refers to an 8-, 9-, 10-, 11-, or 12-memberedbicyclic aromatic ring containing at least 3 double bonds, and whereinthe atoms of the ring include one or more heteroatoms independentlyselected from oxygen, sulfur, and nitrogen. Representative examples ofbicyclic heteroaryl rings include indolyl, benzothienyl, benzofuranyl,indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl,benzoisothiazolyl, benzoisoxazolyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, phthalazinyl, pteridinyl, purinyl,naphthyridinyl, cinnolinyl, thieno[2,3-d]imidazole,thieno[3,2-b]pyridinyl, and pyrrolopyrimidinyl.

Heteroaryl groups of the invention, whether monocyclic or bicyclic, maybe substituted with hydrogen, or optionally substituted with one or moresubstituents independently selected from acyl, acyloxy, alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl,alkyl, alkylcarbonyl, alkylsulfonyl, amido, carboxy, cyano, cycloalkyl,fluoroalkoxy, formyl, haloalkoxy, haloalkyl, halogen, hydroxy,hydroxyalkyl, mercapto, nitro, alkylthio, —NR_(A)R_(B), and(NR_(A)R_(B))carbonyl, Monocyclic heteroaryl or 5- or 6-memberedheteroaryl rings are substituted with 0, 1, 2, 3, 4, or 5 substituents.Bicyclic heteroaryl or 8- to 12-membered bicyclic heteroaryl rings aresubstituted with 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9 substituents.Heteroaryl groups of the present invention may be present as tautomers.

The terms “heterocyclic ring” and “heterocycle”, as used herein, referto a 4- to 12-membered monocyclic or bicyclic ring containing one, two,three, four, or five heteroatoms independently selected from the groupconsisting of nitrogen, oxygen, and sulfur and also containing either atleast one carbon atom attached to four other atoms or one carbon atomsubstituted with an oxo group and attached to two other atoms. Four- andfive-membered rings may have zero or one double bond. Six-membered ringsmay have zero, one, or two double bonds. Seven- and eight-membered ringsmay have zero, one, two, or three double bonds. The non-aromaticheterocycle groups of the invention can be attached through a carbonatom or a nitrogen atom. The non-aromatic heterocycle groups may bepresent in tautomeric form. Representative examples ofnitrogen-containing heterocycles include, but are not limited to,azepanyl, azetidinyl, aziridinyl, azocanyl, dihydropyridazinyl,dihydropyridinyl, dihydropyrimidinyl, morpholinyl, piperazinyl,piperidinyl, pyrrolidinyl, pyrrolinyl, dihydrothiazolyl,dihydropyridinyl, and thiomorpholinyl. Representative examples ofnon-nitrogen containing non-aromatic heterocycles include, but are notlimited to, dioxanyl, dithianyl, tetrahydrofuryl, dihydropyranyl,tetrahydropyranyl, and [1,3]dioxolanyl.

The heterocycles of the invention are substituted with hydrogen, oroptionally substituted with 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9 substituentsindependently selected from acyl, acyloxy, alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl,alkyl, alkylsulfonyl, amido, arylalkyl, arylalkoxycarbonyl, carboxy,cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl,mercapto, nitro, oxo, thioalkoxy, —NR_(A)R_(B), and(NR_(A)R_(B))sulfonyl.

Additional examples of heterocycles include, but are not limited to,azetidin-2-one, azepan-2-one, isoindolin-1,3-dione,(Z)-1H-benzo[e][1,4]diazepin-5(4H)-one, pyridazin-3(2H)-one,pyridin-2(1H)-one, pyrimidin-2(1H)-one, pyrimidin-2,4(1H,3H)-dione,pyrrolidin-2-one, benzo[d]thiazol-2(3H)-one, pyridin-4(1H)-one,imidazolidin-2-one, 1H-imidazol-2(3H)-one, piperidin-2-one,tetrahydropyrimidin-2(1H)-one, 1H-benzo[d]imidazol-2(3H)-one,[1,2,4]thiadiazolonyl, [1,2,5]thiadiazolonyl, [1,3,4]thiadiazinonyl,[1,2,4]oxadiazolonyl, [1,2,5]oxadiazolonyl, [1,3,4]oxadiazinonyl, and1,5-dihydro-benzob[1,4]diazepin-2-on-yl.

The term “hydroxy” as used herein means an —OH group.

The term “hydroxyalkyl” as used herein means at least one hydroxy group,as defined herein, appended to the parent molecular moiety through analkyl group, as defined herein. Representative examples of hydroxyalkylinclude, but are not limited to, hydroxymethyl, 2-hydroxyethyl,2-methyl-2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and2-ethyl-4-hydroxyheptyl.

The term “hydroxy-protecting group”⁷ means a substituent which protectshydroxyl groups against undesirable reactions during syntheticprocedures. Examples of hydroxy-protecting groups include, but are notlimited to, methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl,2-(trimethylsilyl)ethoxymethyl, benzyl, triphenylmethyl,2,2,2-trichloroethyl, t-butyl, trimethylsilyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, methylene acetal, acetonide benzylidene acetal,cyclic ortho esters, methoxymethylene, cyclic carbonates, and cyclicboronates. Hydroxy-protecting groups are appended onto hydroxy groups byreaction of the compound that contains the hydroxy group with a base,such as triethylamine, and a reagent selected from an alkyl halide,alkyl trifilate, trialkylsilyl halide, trialkylsilyl triflate,aryldialkylsilyltriflate, or an alkylchloroformate, CH₂I₂, or adihaloboronate ester, for example with methyliodide, benzyl iodide,triethylsilyltriflate, acetyl chloride, benzylchloride, ordimethylcarbonate A protecting group also may be appended onto a hydroxygroup by reaction of the compound that contains the hydroxy group withacid and an alkyl acetal.

The term “imino” as defined herein means a —C(═NH)— group.

The term “mercapto” as used herein means a —SH group.

The term “—NR_(A)R_(B)” as used herein means two groups, R_(A) andR_(B), which are appended to the parent molecular moiety through anitrogen atom. R_(A) and R_(B) are independently selected from hydrogen,alkyl, acyl, and formyl. Representative examples of —NR_(A)R_(B)include, but are not limited to, amino, dimethylamino, methylamino,acetylamino, and acetylmethylamino.

The term “(NR_(A)R_(B))alkyl” as used herein means an —NR_(A)R_(B)group, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples of(NR_(A)R_(B))alkyl include, but are not limited to,2-(methylamino)ethyl, 2-(dimethylamino)ethyl, 2-(amino)ethyl,2-(ethylmethylamino)ethyl, and the like.

The term “(NR_(A)R_(B))carbonyl” as used herein means an —NR_(A)R_(B)group, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples of(NR_(A)R_(B))carbonyl include, but are not limited to, aminocarbonyl,(methylamino)carbonyl, (dimethylamino)carbonyl,(ethylmethylamino)carbonyl, and the like.

The term “(NR_(A)R_(B))sulfonyl” as used herein means a —NR_(A)R_(B)group, as defined herein, appended to the parent molecular moietythrough a sulfonyl group, as defined herein. Representative examples of(NR_(A)R_(B))sulfonyl include, but are not limited to, aminosulfonyl,(methylamino)sulfonyl, (dimethylamino)sulfonyl and(ethylmethylamino)sulfonyl.

The term “nitro” as used herein means a —NO₂ group.

The term “nitrogen protecting group” as used herein means those groupsintended to protect a nitrogen atom against undesirable reactions duringsynthetic procedures. Nitrogen protecting groups comprise carbamates,amides, N-benzyl derivatives, and imine derivatives. Preferred nitrogenprotecting groups are acetyl, benzoyl, benzyl, benzyloxycarbonyl (Cbz),formyl, phenylsulfonyl, pivaloyl, tert-butoxycarbonyl (Boc),tert-butylacetyl, trifluoroacetyl, and triphenylmethyl (trityl).Nitrogen-protecting groups are appended onto primary or secondary aminogroups by reacting the compound that contains the amine group with base,such as triethylamine, and a reagent selected from an alkyl halide, analkyl trifilate, a dialkyl anhydride, for example as represented by(alkyl-O)₂C═O, a diaryl anhydride, for example as represented by(aryl-O)₂C═O, an acyl halide, an alkylchloroformate, or analkylsulfonylhalide, an arylsulfonylhalide, or halo-CON(alkyl)₂, forexample acetylchloride, benzoylchloride, benzylbromide,benzyloxycarbonylchloride, formylfluoride, phenylsulfonylchloride,pivaloylchloride, (tert-butyl-O—C—O)₂O, trifluoroacetic anhydride, andtriphenylmethylchloride.

The term “oxo” as used herein means (═O).

The term “sulfonyl” as used herein means a —S(O)₂— group.

The term “thioalkoxy” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through a sulfur atom.Representative examples of thioalkoxy include, but are no limited to,methylthio, ethylthio, and propylthio.

As used herein, the term “antagonist” encompasses and describescompounds that prevent receptor activation by an H₃ receptor agonistalone, such as histamine, and also encompasses compounds known as“inverse agonists” Inverse agonists are compounds that not only preventreceptor activation by an H₃ receptor agonist, such as histamine, butalso inhibit intrinsic H₃ receptor activity

Compounds of the Invention

Compounds of the invention can have the formula (I) as described above.

In compounds of formula (I), one of R₁ and R₂ is a group of the formula-L₂-R_(6a)-L₃-R_(6b). The other group of R₁ and R₂ is selected fromhydrogen, alkyl, alkoxy, halogen, cyano, and thioalkoxy. Preferably, R₁is -L₂-R_(6a)-L₃-R_(6b) and R₂ is selected from hydrogen, alkyl, alkoxy,halogen, cyano, and thioalkoxy. When one of R₁ or R₂ is-L₂-R_(6a)-L₃-R_(6b), then the other is preferably hydrogen.

L₂ is selected from a bond, alkylene, —O—, —C(═O)—, —S—, —NH—,—N(R₁₆)C(═O)—, —C(═O)N(R₁₆), and —N(alkyl)-. It is preferred that L₂ isa bond.

L₃ is selected from a bond, alkylene, —O—, —C(═O)—, —S—, —N(R₁₆)C(═O)—,—C(═O)N(R₁₆), and —N(R₅)—, wherein R₁₅ is selected from hydrogen, alkyl,acyl, alkoxycarbonyl, amido, and formyl. It is preferred that L₃ is abond.

R_(6a) is selected from a 5- to 6-membered heteroaryl ring, cyanophenyl,an 8- to 12-membered bicyclic heteroaryl ring, and a 4- to 12-memberedheterocyclic ring. The 5- to 6-membered heteroaryl ring, 8- to12-membered bicyclic heteroaryl ring, and 4- to 12-membered heterocyclicring for R_(6a) can be substituted or unsubstituted.

R_(6b) is selected from hydrogen, a 5- to 6-membered heteroaryl ring, anaryl ring, an 8- to 12-membered bicyclic heteroaryl ring, and a 4- to12-membered heterocyclic ring. The 5- to 6-membered heteroaryl ring,aryl ring, 8- to 12-membered bicyclic heteroaryl ring, and 4- to12-membered heterocyclic ring for R_(6b) can be substituted orunsubstituted.

Specific examples of 5- to 6-membered heteroaryl rings suitable forR_(6a) and R_(6b) include, but are not limited to, furyl, imidazolyl,isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, [1,2,3]thiadiazolyl,[1,2,3]oxadiazolyl, thiazolyl, thienyl, [1,2,3]triazinyl,[1,2,4]triazinyl, [1,3,5]triazinyl, [1,2,3]triazolyl, and[1,2,4]triazolyl. Preferred 5- to 6-membered heteroaryl rings are, forexample, pyrimidinyl, pyridinyl, and pyrazolyl. Each of the 5- to6-membered heteroaryl rings is independently unsubstituted orsubstituted with substituents as described herein, for example as in theExamples or the Definitions.

Examples of 8- to 12-membered bicyclic heteroaryl rings suitable forR_(6a) and R_(6b) include, but are not limited to, indolyl,benzothienyl, benzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl,benzoxazolyl, benzoisothiazolyl, benzoisoxazolyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pteridinyl,purinyl, naphthyridinyl, cinnolinyl, thieno[2,3-d]imidazole,thieno[3,2-b]pyridinyl, and pyrrolopyrimidinyl. Preferred 8- to12-membered bicyclic heteroaryl rings are, for example, benzothiazolyland thieno[3,2-b]pyridinyl. Each of the 8- to 12-membered bicyclicheteroaryl rings is independently unsubstituted or substituted withsubstituents as described herein, for example as in the Examples or theDefinitions.

Examples of 4- to 12-membered heterocyclic rings suitable for R_(6a) andR_(6b) include, but are not limited to, azepanyl, azetidinyl,aziridinyl, azocanyl, dihydropyridazinyl, dihydropyridinyl,dihydropyrimidinyl, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl,pyrrolinyl, dihydrothiazolyl, dihydropyridinyl, thiomorpholinyl,dioxanyl, dithianyl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl,[1,3]dioxolanyl, azetidin-2-onyl, azepan-2-onyl, isoindolin-1,3-dionyl,(Z)-1H-benzo[e][1,4]diazepin-5(4H)-onyl, pyridazin-3(2H)-onyl,pyridin-2(1H)-onyl, pyrimidin-2(1H)-onyl, pyrimidin-2,4(1H,3H)-dionyl,pyrrolidin-2-onyl, benzo[d]thiazol-2(3H)-onyl, pyridin-4(1H)-onyl,imidazolidin-2-onyl, 1H-imidazol-2(3H)-onyl, piperidin-2-onyl,tetrahydropyrimidin-2(1H)-onyl, [1,2,4]thiadiazolonyl,[1,2,5]thiadiazolonyl, [1,3,4]thiadiazinonyl, [1,2,4]oxadiazolonyl,[1,2,5]oxadiazolonyl, [1,3,4]oxadiazinonyl, and1H-benzo[d]imidazol-2(3H)-onyl. Preferred 4- to 12-membered heterocyclicrings are azetidin-2-onyl, azepan-2-onyl, pyridazin-3(2H)-onyl,pyrrolidin-2-onyl, and piperidin-2-onyl. Each of the heterocyclic ringsis independently unsubstituted or substituted with substituents asdescribed herein, for example as in the Examples or the Definitions.

In one preferred embodiment, the group R₁ is -L₂-R_(6a)-L₃-R_(6b),wherein L₂ is a bond; R_(6b) is hydrogen, L₃ is a bond; R_(6a) isselected from a 5- or 6-membered heteroaryl ring, and R₂, R₃, R_(3a),R_(3b), R₄, R₅, and L are as previously described

In another preferred embodiment, the group R₁ is -L₂-R_(6a)-L₃-R_(6b),wherein L₂ is a bond; R_(6b) is hydrogen, L₃ is a bond, R_(6a) isselected from a 8- to 12-membered bicyclic heteroaryl ring; and R₂, R₃,R_(3a), R_(3b), R₄, R₅, and L are as previously described herein.

In another preferred embodiment, the group R₁ is -L₂-R_(6a)-L₃-R_(6b),wherein L₂ is a bond; R_(6b) is hydrogen; L₃ is a bond; R_(6a) isselected from a 4- to 12-membered heterocyclic ring, and R₂, R₃, R_(3a),R_(3b), R₄, R₅, and L are as previously described herein.

In another preferred embodiment, the group R₁ is -L₂-R_(6a)-L₃-R_(6b),wherein L₂ is a bond, R_(6b) is hydrogen, L₃ is a bond, R_(6a) ispyridazin-3(2H)-onyl; and R₂, R₃, R_(3a), R_(3b), R₄, R₅, and L are aspreviously described herein.

Each of R₃, R_(3a), and R_(3b) are each independently selected from thegroup consisting of hydrogen, alkyl, trifluoroalkyl, trifluoroalkoxy,alkoxy, halogen, cyano, and thioalkoxy. Preferably, R₃, R_(3a), andR_(3b) are hydrogen, or, one of R₃, R_(3a), and R_(3b) is halogen andthe others are hydrogen. The preferred halogen is fluorine.

R₄ and R₅ are each independently selected from the group consisting of aalkyl, fluoroalkyl, hydroxyalkyl, alkoxyalkyl, and cycloalkyl.Alternatively, R₄ and R₅ taken together with the nitrogen atom to whicheach is attached to form a non-aromatic ring of the formula:

R₇, R₈, R₉, and R₁₀ are each independently selected from hydrogen,hydroxyalkyl, fluoroalkyl, cycloalkyl, and alkyl.

R_(x) and R_(y) at each occurrence are independently selected from thegroup consisting of hydrogen, hydroxy, hydroxyalkyl, alkyl, alkoxy,alkylamino, fluoro, and dialkylamino.

Preferably, at least one carbon in a group of formula (a) issubstituted, such that either one of R₇, R₈, R₉, or R₁₀, or one of R_(x)and R_(y) is other than hydrogen. The preferred substituents for R₇, R₈,R₉, or R₁₀, when substituted, are hydroxyalkyl, fluoroalkyl, or alkyl.The preferred alkyl group is more particularly, methyl. The preferredsubstituents for R_(x) or R_(y), when substituted, are alkyl, fluoro, orhydroxy.

Groups of formula (a) are preferred for R₄ and R₅ when taken together toform a non-aromatic ring. The preferred group for R₄ and R₅ when takentogether with the nitrogen atom to which each is attached to form agroup of formula (a) is (2R)-methylpyrrolidine or(2S)-methylpyrrolidine.

R₁₁, R₁₂, R₁₃, and R₁₄ are each independently selected from hydrogen,hydroxyalkyl, alkyl, and fluoroalkyl. Preferably, at least threesubstituents selected from R₁₁, R₁₂, R₁₃, and R₁₄ are hydrogen.

Q is selected from O and S. The preferred atom for Q is oxygen.

The preferred group for R₄ and R₅ when taken together with the nitrogenatom to which each is attached to form a group of formula (b) ismorpholinyl.

The variable m is an integer from 1 to 5.

L is —[C(R₁₆)(R₁₇)]_(k), wherein R₁₆ and R₁₇ at each occurrence areindependently selected from hydrogen and alkyl, and k is 1, 2 or 3.Preferably, k is 1 or 2.

One embodiment relates to compounds of formula (II):

wherein L, R₁, R₂, R₃, R_(3a), R_(3b), R₄, and R₅ are as previouslydescribed.

In one preferred embodiment of compounds of the invention of formula(II), the group R₁ is -L₂-R_(6a)-L₃-R_(6b), wherein L₂ is a bond; R_(6b)is hydrogen; L₃ is a bond; R_(6a) is selected from a 5- or 6-memberedheteroaryl ring, or a 4- to 12-membered heterocyclic ring; R₄ and R₅,when taken together with the nitrogen atom to which each is attached,form a 4- to 8-membered non-aromatic ring represented by formula (a),and R₂, R₃, R_(3a), R_(3b), and L are as previously described.

Another embodiment relates to compounds of formula (III):

wherein L, R₁, R₂, R₃, R_(3a), R_(3b), R₄, and R₅ are as previouslydescribed.

In one preferred embodiment of compounds of the invention of formula(III), the group R₁ is -L₂-R_(6a)-L₃-R_(6b), wherein L₂ is a bond;R_(6b) is hydrogen L₃ is a bond, R_(6a) is selected from a 5- or6-membered heteroaryl ring, or a 4- to 12-membered heterocyclic ring; R₄and R₅ when taken together with the nitrogen atom to which each isattached to form a 4- to 8-membered non-aromatic ring represented byformula (a), and R₂, R₃, R_(3a), R_(3b), and L are as previouslydescribed.

Specific examples of compounds contemplated as within the scope of theinvention include, but are not limited to, the following:

-   4′-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrile;-   4′-((1S,2S)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrile;-   4′-((1R,2R)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrile;-   4′-((1R,2R)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrile,-   4′-{(1S,2S)-2-[(2-methylpyrrolidin-1-yl)methyl]cyclopropyl}-1,1′-biphenyl-4-carbonitrile,-   5-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidine,-   2-methoxy-5-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidine,-   2,6-dimethyl-3-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridine,-   2-methoxy-5-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridine;-   5-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidine;-   5-[4-((1R,2R)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidine;-   5-[4-((1R,2R)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidine;-   2,4-dimethoxy-5-[4-((1R,2R)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidine;-   2,4-dimethoxy-5-[4-((1R,2R)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidine,-   2,4-dimethoxy-5-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidine;-   2,4-dimethoxy-5-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidine;-   2-[4-((1R,2R)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-one;-   2-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-one;-   2-methyl-5-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]-1,3-benzothiazole;-   1,3,5-trimethyl-4-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]-1H-pyrazole;-   2,6-dimethyl-3-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridine;-   N-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidin-5-amine;-   4′-((1R,2S)-2-{2-[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrile,-   4′-((1S,2R)-2-{2-[(2R)-2-methylpyrrolidin-1-yl]ethyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrile,-   4′-[(trans)-2-(2-pyrrolidin-1-ylethyl)cyclopropyl]-1,1′-biphenyl-4-carbonitrile;-   N-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]-5-(trifluoromethyl)thieno[3,2-b]pyridine-6-carboxamide;-   N-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]isonicotinamide;-   2-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-one;-   1-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]piperidin-2-one;-   1-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]azepan-2-one;-   1-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrrolidin-2-one,-   1-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]azetidin-2-one;-   1-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]azetidin-2-one,-   1-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]azepan-2-one;-   1-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]piperidin-2-one,-   1-[4-((1S,2S)-2-([(2S)-2-methylpyrrolidin-1-yl]methyl)cyclopropyl)phenyl]pyrrolidin-2-one;-   N-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]acetamide;    and-   N-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]-1H-1,2,4-triazole-3-carboxamide.

The following compounds can be made according to the methods and Schemesdescribed herein:

-   5-(pyrrolidin-1-ylcarbonyl)-2-{4-[(trans)-2-(2-pyrrolidin-1-ylethyl)cyclopropyl]phenyl}pyridine;-   4′-{(1S,2R)-2-[2-(2-methylpyrrolidin-1-yl)ethyl]cyclopropyl}-1,1′-biphenyl-4-carbonitrile;-   4′-((1S,2R)-2-{2-[(3R)-3-hydroxypyrrolidin-1-yl]ethyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrile;-   4′-((1S,2R)-2-{2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]ethyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrile;-   4′-[(1S,2R)-2-(2-azepan-1-ylethyl)cyclopropyl]-1,1′-biphenyl-4-carbonitrile,    and-   4′-[(1S,2R)-2-(2-morpholin-4-ylethyl)cyclopropyl]-1,1′-biphenyl-4-carbonitrile.

More preferred embodiments are compounds selected from:

-   2-methoxy-5-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidine,-   2-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-one;    and-   2-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-one,    or salts thereof.

Another more preferred embodiment relates to the compound2-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-oneor a salt thereof.

Compounds of the invention were named by ACD/ChemSketch version 5.01(developed by Advanced Chemistry Development, Inc, Toronto, ON, Canada)or were given names consistent with ACD nomenclature; Alternatively,compounds were assigned names using ChemDraw (Cambridgesoft). Thepractice of assigning names to chemical compounds from structures, andof assigning chemical structures from given chemical names is well knownto those of ordinary skill in the art.

Compounds of the invention may exist as stereoisomers wherein,asymmetric or chiral centers are present. These stereoisomers are “R” or“S” depending on the configuration of substituents around the chiralcarbon atom. The terms “R” and “S” used herein are configurations asdefined in IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, in Pure Appl. Chem., 1976, 45: 13-30. The inventioncontemplates various stereoisomers and mixtures thereof and these arespecifically included within the scope of this invention. Stereoisomersinclude enantiomers and diastereomers, and mixtures of enantiomers ordiastereomers. Individual stereoisomers of compounds of the inventionmay be prepared synthetically from commercially available startingmaterials which contain asymmetric or chiral centers or by preparationof racemic mixtures followed by resolution well-known to those ofordinary skill in the art. These methods of resolution are exemplifiedby (1) attachment of a mixture of enantiomers to a chiral auxiliary,separation of the resulting mixture of diastereomers byrecrystallization or chromatography and optional liberation of theoptically pure product from the auxiliary as described in Furniss,Hannaford, Smith, and Tatchell, “Vogel's Textbook of Practical OrganicChemistry”, 5th edition (1989), Longman Scientific & Technical, EssexCM20 2JE, England, or (2) direct separation of the mixture of opticalenantiomers on chiral chromatographic columns or (3) fractionalrecrystallization methods.

Compounds of the invention may exist as cis or trans isomers, whereinsubstituents on a ring may attached in such a manner that they are onthe same side of the ring (cis) relative to each other, or on oppositesides of the ring relative to each other (trans). For example,cyclobutanes and cyclohexanes may be present in the cis or transconfiguration, and may be present as a single isomer or a mixture of thecis and trans isomers. Individual cis or trans isomers of compounds ofthe invention may be prepared synthetically from commercially availablestarting materials using selective organic transformations, or preparedin single isomeric form by purification of mixtures of the cis and transisomers. Such methods are well known to those of ordinary skill in theart, and may include separation of isomers by recrystallization orchromatography.

It should be understood that the compounds of the invention may possesstautomeric forms, as well as geometric isomers, and that these alsoconstitute an aspect of the invention. It is also understood that thecompounds of the invention may exist as isotopomers, wherein atoms mayhave different weights; for example, hydrogen, deuterium and tritium, or¹²C, ¹¹C and ¹³C, or ¹⁹F and ¹⁸F.

Methods for Preparing Compounds of the Invention

The compounds of the invention can be better understood in connectionwith the following synthetic schemes and methods which illustrate ameans by which the compounds can be prepared.

Abbreviations which have been used in the descriptions of the schemesand the examples that follow are: Ac for acetyl, atm for atmosphere(s),AIBN for 2,2′-azobis(2-methylpropionitrile); BINAP for2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; Boc for butyloxycarbonyl;Bu for butyl; dba for dibenzylidineactone; DBU for1,8-diazabicyclo[5.4.0]undec-7-ene, DCM for dichloromethane, DIBAL-H fordiisobutylaluminum hydride; DMAP for 4-(N,N-dimethylamino)pyridine; DMEfor 1,2-dimethoxyethane; DMF for N,N-dimethylformamide; DMSO fordimethylsulfoxide; dppf for 1,1′-bis(diphenylphosphino)ferrocene; EDTAfor ethylenediaminetetraacetic acid, Et for ethyl; EtOH for ethanol;EtOAc for ethyl acetate, HPLC for high pressure liquid chromatography;IPA for isopropyl alcohol, IPAC or IPAc for isopropyl acetate, LDA forlithium diisopropylamide; NBS for N-bromosuccinimide; NIS forN-iodosuccinimide; Me for methyl, MeOH for methanol; Ms formethanesulfonyl; MTBE for tert-butyl methyl ether, Pd for palladium, Phfor phenyl; tBu for tert-butyl; TE buffer for a combination Tris andEDTA buffer, TEA for triethylamine; TFA for trifluoroacetic acid; THFfor tetrahydrofuran; Tris for 2-amino-2-hydroxymethyl-1,3-propanediol;and Ts for para-toluenesulfonyl, rt for “room temperature” or ambienttemperature suitably ranging 15-40° C. As identifiers of compoundsavailable from descriptions reported in the literature or availablecommercially, CAS numbers may be used; CAS numbers are identifiernumbers assigned to compounds by Chemical Abstracts Service of theAmerican Chemical Society, and are well known to those of ordinary skillin the art.

The compounds of this invention can be prepared by a variety ofsynthetic procedures. Representative procedures are shown in, but arenot limited to, Schemes 1-7.

Compounds of formulas (13) and (14), wherein R₃, R_(3a), R_(3b), R₄ andR₅ are as defined in formula (I), R₁ is -L₂-R_(6a)-L₃-R_(6b), and R₂ ishydrogen, alkyl, alkoxy, halogen, cyano, or thioalkoxy, wherein L₂ is abond, —N(H), —N(alkyl), —O—, or —S—, and R_(6a), L₃ and R_(6b) are asdefined in formula (I), can be prepared as described in Scheme 1. Estersof formula (1) wherein R is a lower alkyl, and X is Cl, Br, I, ortriflate, purchased or prepared using methodologies known to those ofordinary skills in the art, can be reduced with a reducing agent suchas, but not limited to, DIBAL to provide allylic alchols of formula (2).Allylic alchols of formula (2) can be converted to cyclopropyl alcoholsof formula (5) and (6) following the methodology of A Charette, J. Org.Chem. 1998. The cyclopropyl alcohols of formulas (5) and (6) can beoxidized via a reaction known as Swern oxidation, by an agent, such as,but not limited to, DMSO and oxalyl chloride to provide aldehydes offormula (7) and (8). References describe this methodology may be foundin the following: Tidwell, Thomas T. Organic Reactions (New York)(1990), 39 297-572 and the references cited in the article. Aldehydes offormulas (7) and (8) can be treated with reducing agents such as, butnot limited to, sodium cyanoborohydride or sodium triacetoxyborohydride,in the presence of an amine of formula (9), via a reaction known asreductive amination, to provide amines of formula (10) and (11)respectively. References that describe this methodology may be found inthe following. M. D. Bomann et al., J. Org. Chem., 60:5995-5960 (1995);A. E Moormann et al., Synth. Commun., 23.789-795 (1993), and A, Pelteret al., J. Chem. Soc., PT I, 4:717-720 (1984); A. F. Abdel-Magid et al.,J. Org. Chem. 1996, 61, 3849-3862.

The Suzuki reaction can be used to convert amines of formula (10) and(11) respectively to compounds of formula (13) and (14), wherein R₃,R_(3a), R_(3b), R₄, and R₅ are as defined in formula (I), R₂ ishydrogen, alkyl, alkoxy, halogen, cyano, or thioalkoxy, and R₁ is-L₂-R_(6a)-L₃-R_(6b), wherein L₂ is a bond and R_(6a), and L₃ and R_(6b)are as defined in formula (I). In such a Suzuki reaction, amines offormula (13) and (14), wherein X is triflate, 1, Br, or Cl can bereacted with boronic acids or boronic esters of formula (12) whereinR₁₀₁ is hydrogen or alkyl, a metal catalyst such as, but not limited to,palladium diacetate or Pd(PPh₃)₄, optionally with a Pd ligand added suchas 2-(dicyclohexylphosphino)biphenyl or tris(2-furyl)phosphine, and abase such as, but not limited to, aqueous 0.2 M K₃PO₄ or sodiumcarbonate.

Alternatively, pinacol borane reagents such as, but not limited to,those represented by formula (12a) can be used in place of boronic acidsor esters of formula (12) in the Suzuki reaction. References thatdescribe the preparation and use of such reagents useful in the Suzukireaction methodogy may be found in the following: N. Miyaura et al.,Chem. Rev. 95:2457 (1995) and references cited in the article.

There are many aryl, heteroaryl, and heterocyclic boronic acids andboronic acid esters that are available commercially or that can beprepared as described in the scientific literature of synthetic organicchemistry. Examples of boronic acid and boronic acid ester reagents forthe synthesis of compounds of formula (1) are provided, but not limitedto, reagents shown in Table 1, below, and the following description

TABLE 1 Examples of Boronic Acid and Boronic Acid Ester Reagents BoronicAcid or Boronic Commercial Source, Chemical Abstracts Acid Ester Number(CAS #), or Literature Reference 2-pyrimidinone-5- CAS #373384-19-1boronic acid 2-methoxypyrimidine-5- Frontier Scientific, Inc., Logan,UT, USA boronic acid 1H-pyrimidine-2,4-dione- Specs, Fleminglaan, theNetherlands 5-boronic acid CAS #70523-22-7, Schinazi, Raymond F,;Prusoff, William H., Synthesis of 5- (dihydroxyboryl)-2′-deoxyuridineand related boron-containing pyrimidines, Journal of Organic Chemistry(1985), 50(6), 841-7. pyridine-3-boronic CAS #1692-25-7, FrontierScientific, Inc., acid Logan, UT, USA 2,4-dimethoxypyrimidine- CAS#89641-18-9, Frontier Scientific, Inc., 5-boronic acid Logan, UT, USA2-methoxy-5-pyridine Digital Specialty Chemicals, Dublin, NH; boronicacid CAS #163105-89-3; New shelf-stable halo- and alkoxy-substitutedpyridylboronic acids and their Suzuki cross-coupling reactions to yieldheteroarylpyridines, Parry, Paul R.; Bryce, Martin R.; Tarbit, Brian,Department of Chemistry, Synthesis (2003), (7), 1035- 1038;Functionalized Pyridylboronic Acids and Their Suzuki Cross-CouplingReactions To Yield Novel Heteroarylpyridines, Parry, Paul R.; Wang,Changsheng; Batsanov, Andrei S.; Bryce, Martin R.; Tarbit, Brian,Journal of Organic Chemistry (2002), 67(21), 7541-7543,pyrimidine-5-boronic acid CAS #109299-78-7, S. Gronowitz, et al., “Onthe synthesis of various thienyl- and selenienylpyrimidines”, Chem. Scr.26(2): 305-309 (1986). pyrimidine-5-boronic Umemoto, et al., Angew.Chem. Int. Ed. acid, pinacol ester 40(14): 2620-2622 (2001).2-methylpyridine-5- SYNCHEM OHG boronic acid hydrateHeinrich-Plett-Strassse 40; Kassel, D- 34132; Germany; CAS #659742-21-92H-Pyran, 3,6-dihydro-4- CAS # 287944-16-5, Murata, Miki; Oyama,(4,4,5,5-tetramethyl-1,3,2- Takashi; Watanabe, Shinji; Masuda,dioxaborolan-2-yl) Yuzuru, Synthesis of alkenylboronates viapaliadium-catalyzed borylation of alkenyl triflates (or iodides) withpinacolborane. Synthesis(2000), (6), 778-780. 1(2H)-PyridinecarboxylicCAS # 286961-14-6; A versatile synthesis acid, 3,6-dihydro-4- of4-aryltetrahydropyridines via palladium (4,4,5,5-tetramethyl- mediatedSuzuki cross-coupling with cyclic 1,3,2-dioxaborolan- vinyl boronates,Eastwood, Paul R., 2-yl)-, Discovery Chemistry, Aventis Pharma,1,1-dimethylethyl ester Essex, UK., Tetrahedron Letters (2000), 41(19),3705-3708. (5-cyano-3-pyridinyl)- CAS # 497147-93-0; boronic acidChemstep Institut du PIN - University Bordeaux 1 351 cours de laliberation Talence Cedex, 33450 France

Boronic acids or boronic acid esters of formula (12), and (12a) can beprepared from corresponding halides or triflates via either (1) metalexchange with an organo lithium agent followed with addition of alkylborate or pinacolborate or (2) cross coupling with a reagent such as,but not limited to, bis(pinacolato)diboron (CAS #73183-34-3). Referencesthat describe the first methodology may be found in the following: B. T.O'Neill, et al., Organic Letters, 2:4201 (2000); M. D. Sindkhedkar, etal., Tetrahedron, 57:2991 (2001); W. C. Black, et al., J. Med. Chem.,42:1274 (1999); R. L. Letsinger et al., J. Amer. Chem. Soc., 81:498-501(1959), and F. I. Carroll et al., J. Med. Chem., 44:2229-2237 (2001).References that describe the second methodology may be found in thefollowing T. Ishiyama et al., Tetrahedron, 57:9813-9816 (2001), T.Ishiyama et al., J. Org. Chem., 60:7508-7510 (1995); and Takagi et al.,Tetrahedron Letters, 43:5649-5651 (2002).

Another method for preparation of boronic acids and boronic acid estersis the reaction described in O. Baudoin, et al., J. Org. Chem.,65:9268-9271 (2000), in which aryl and heteroaryl halides or triflatesare reacted with a dialkyloxyborane such as pinacolborane, in thepresence of triethylamine and palladium (II) acetate in dioxane.

Alternatively, utilizing other coupling methods such as Stille coupling,compounds of formulas (13) and (14) wherein R₃, R_(3a), R_(3b), R₄, andR₅ are as defined in formula (I), R₂ is hydrogen, alkyl, alkoxy,halogen, cyano or thioalkoxy, and R₁ is -L₂-R_(6a)-L₃-R_(6b), wherein L₂is a bond and R_(6a), L₃, and R_(6b) are as defined in formula (I), canbe prepared from amines of formulas (10) and (11) respectively, bytreatment with organostannanes of formula (R₁₀₂)₃SnR₁, wherein R₁₀₂ isalkyl or aryl, in the presence of a palladium source such astris(dibenzylidineacetone)dipalladium (CAS #52409-22-0) or palladiumdiacetate, and a ligand such as tri(2-furyl)phosphine (CAS #5518-52-5)or triphenylarsine. The reaction is generally performed in a solventsuch as DMF at a temperature from about 25° C. to about 150° C. Suchmethods are described, for instance, in J. K. Stille. Angew. Chem. Int.Ed. 25:508 (1986) and T. N. Mitchell, Synthesis, 803 (1992).

While many stannanes are commercially available or described in theliterature that support the Stille coupling reaction where compounds offormulas (10) and (11) can be transformed to compounds of formulas (13)and (14), respectively, it is also possible to prepare new stannanesfrom arylhalides, aryltriflates, heteroarylhalides, andheteroaryltriflates by reaction with hexa-alkyl distannanes of formula((R₁₀₂)₃Sn)₂ wherein R₁₀₂ is alkyl or aryl, in the presence of apalladium source like Pd(Ph₃P)₄. Example of hexa-alkyl distannanesinclude, but not limited to, hexamethyldistannane (CAS #661-69-8). Suchmethods are described, for instance in Krische, et. al., HelveticaChimica Acta 81(11):1909-1920 (1998), and in Benaglia, et al.,Tetrahedron Letters 38:4737-4740 (1997). These reagents can be reactedwith (10) and (11) to afford compounds of formulas (13) and (14)respectively as described under Stille conditions, or for example underthe conditions reported by A. F. Littke et al., J. of Amer. Chem. Soc.124:6343-6348 (2002).

Compounds of formulas (13) and (14) wherein R₃, R_(3a), R_(3b), R₄, andR₅ are as defined in formula (I), R₂ is hydrogen, alkyl, alkoxy,halogen, cyano or thioalkoxy, and R₁ is -L₂-R_(6a)-L₃-R_(6b), wherein L₃and R_(6b) are as defined in formula (I), L₂ is a bond, and R_(6a) is anitrogen-containing heteroaryl or heterocyclic ring linked to the parentmoiety through the nitrogen, can be prepared by heating compounds offormulas (10) and (11) respectively, with heteroaryl or heterocyclicrings of formula H—R_(6a)L₃R_(6b) wherein H is a hydrogen on thenitrogen atom, in the presence of a base such as, but not limited to,sodium t-butoxide or cesium carbonate, a metal catalyst such as, but notlimited to copper metal or CuI, palladium diacetate, and optionally witha ligand such as, but not limited to, BINAP or tri-tertbutylphosphine.The reaction can be conducted in a solvent such as, but not limited to,dioxane, toluene or pyridine. References that describe these methods maybe found in the following. J. Hartwig et al., Angew. Chem. Int. Ed.37:2046-2067 (1998); J. P. Wolfe et al., Acc. Chem. Res., 13:805-818(1998); M. Sugahara et al., Chem. Pharm. Bull., 45:719-721 (1997), J. P.Wolfe et al., J. Org. Chem., 65:1158-1174 (2000); F. Y. Kwong et al.,Org. Lett., 4.581-584 (2002); A. Klapars et al., J. Amer. Chem. Soc.,123:7727-7729 (2001); B. H. Yang et al., J. Organomet. Chem.,576:125-146 (1999); and A. Kiyomori et al., Tet. Lett., 40:2657-2640(1999).

Compounds of formulas (13) and (14) wherein R₃, R_(3a), R_(3b), R₄, andR₅ are as defined in formula (I), R₂ is hydrogen, alkyl, alkoxy,halogen, cyano, or thioalkoxy, and R₁ is -L₂-R_(6a)-L₃-R_(6b), whereinL₂ is —NH— or —N(alkyl)-, and R_(6a), R_(6b) and L₃ are as defined for acompound of formula (I) can be prepared by heating compounds of formula(10) and (11) respectively, with a compound of formulaH₂N—R_(6a)-L₃-R_(6b) or HN(alkyl)-R_(6a)-L₃-R_(6b) with a base such as,but not limited to, sodium t-butoxide or cesium carbonate in thepresence of a metal catalyst such as, but not limited to, copper metalor CuI, palladium diacetate, and also optionally with a ligand such as,but not limited to, BINAP, or tri-tert-butylphosphine. The reaction canbe performed in a solvent such as dioxane, toluene, or pyridine,References that describe these methodologies may be found in thefollowing. J. Hartwig, et al., Angew. Chem. Int. Ed., 37:2046-2067(1998), J. P. Wolfe et al., Acc. Chem. Res., 13:805-818 (1998); J. P.Wolfe et al., J. Org. Chem., 65:1158-1174 (2000), F. Y Kwong et al.,Org. Lett., 4.581-584 (2002), and B. H. Yang et al., J. Organomet.Chem., 576.125-146 (1999).

Compounds of formulas (13) and (14) wherein R₃, R_(3a), R_(3b), R₄ andR₅ are as defined in formula (I), R₂ is hydrogen, alkyl, alkoxy,halogen, cyano, or thioalkoxy, and R₁ is L₂-R_(6a)-L₃-R_(6b), wherein L₂is oxygen and R_(6a), and L₃ and R_(6b) are as defined in formula (I)can be prepared by heating compounds of formula (10) and (11)respectively with a compound of formula HOR_(6a)-L₃-R_(6b) using a basesuch as, but not limited to, sodium hydride in a solvent such as tolueneor N,N-dimethylformamide, in the presence of a metal containing catalystsuch as CuI or palladium diacetate. References that describe thesemethodologies may be found in the following: J. Hartwig et al., Angew.Chem. Int. Ed., 37:2046-2067 (1998); K. E. Torraca et al., J. Amer.Chem. Soc., 123:10770-10771 (2001); S. Kuwabe et al., J. Amer. Chem.Soc., 123.12202-12206 (2001); K. E. Toracca et al, J. Am. Chem. Soc.,122.12907-12908 (2000), R. Olivera et al., Tet. Lett., 41:4353-4356(2000); J.-F. Marcoux et al., J. Am. Chem. Soc., 119:10539-10540 (1997);A. Aranyos et al., J. Amer. Chem. Soc., 121:4369-4378 (1999), T. Satohet al., Bull. Chem. Soc. Jpn., 71:2239-2246 (1998); J. F. Hartwig,Tetrahedron Lett., 38.2239-2246 (1997); M. Palucki et al., J. Amer.Chem. Soc., 119.3395-3396 (1997); N. Haga et al, J. Org. Chem.,61:735-745 (1996), R. Bates et al., J. Org. Chem., 47:4374-4376 (1982);T. Yamamoto et al., Can. J. Chem., 61.86-91 (1983); A. Aranyos et al.,J. Amer. Chem. Soc., 121:4369-4378 (1999); and E. Baston et al., Synth.Commun., 28:2725-2730 (1998).

Compounds of formulas (13) and (14) wherein R₃, R₃₁, R_(3b), R₄ and R₅are as defined in formula (I), R₂ is hydrogen, alkyl, alkoxy, halogen,cyano, or thioalkoxy, and R₁ is L₂-R_(6a)-L₃-R_(6b), wherein L₂ issulfur and R_(6a), and L₃ and R_(6b) are as defined for a compound offormula (1) can be prepared by heating compounds of formula (10) and(11) respectively with a compound of formula HSR_(6a)-L₃-R_(6b) in thepresence of a base, and with or without a metal catalyst such as CuI orpalladium diacetate, in a solvent such as dimethylformamide or toluene.References that describe these methodologies may be found in thefollowing: G. Y. Li et al., J. Org. Chem., 66:8677-8681 (2001), Y. Wanget al., Bioorg. Med. Chem. Lett., 11:891-894 (2001); G. Liu et al., J.Med. Chem., 44:1202-1210 (2001); G. Y. Li et al., Angew. Chem. Int. Ed.,40:1513-1516 (2001), U. Schopfer et al., Tetrahedron, 57:3069-3074(2001); and C. Palomo et al., Tet. Lett., 41.1283-1286 (2000); A Pelteret al., Tet. Lett., 42.8391-8394 (2001); W. Lee et al., J. Org. Chem.,66:474-480 (2001); and A. Toshimitsu et al., Het. Chem., 12:392-397(2001).

Similarly, compounds of formulas (24) and (25) wherein R₃, R_(3a),R_(3b), R₄ and R₅ are as defined in formula (I), R₁ is hydrogen, alkyl,alkoxy, halogen, cyano, or thioalkoxy, and R₂ is -L-R_(6a)-L₃-R_(6b),wherein L₂ is a bond, —N(H), —N(alkyl), —O—, or —S—, and R_(6a), L₃, andR_(6b) are as defined in formula (I), can be prepared as described inScheme 2, from compounds of formula (15) wherein R is a lower alkyl, Xis Cl, Br, I, or triflate, using the reaction conditions that areoutlined in Scheme 1, except for substituting boronic acid or esters offormula (23) for (12) and pinacol borane reagents of formula (23a) for(12a) for the Suzuki reactions, and except for substitutingorganostannes of formula (R₁₀₂)₃SnR₂ for (R₁₀₂)₃SnR₁ for Stille couplingReferences that describe the Suzuki reaction methodology may be found inthe following: N Miyaura et al., Chem. Rev. 95:2457 (1995) andreferences cited in the article.

Compounds of formulas (32) and (33), wherein R₃, R_(3a), R_(3b), R₄, andR₅ are as defined in formula (I), R₁ is -L₂-R_(6b)-L₃-R_(6b), and R₂ ishydrogen, alkyl, alkoxy, halogen, cyano, or thioalkoxy, wherein L₂ is abond, —N(H), —N(alkyl), —O—, or —S—, and R_(6a), L₃, and R_(6b) are asdefined in formula (I), can be prepared as described in Scheme 3,Aldehydes of formulas of (24) and (25), prepared according to thereaction conditions in Scheme 1 from esters of formula (1) wherein R isa lower alkyl, can be treated with methyltriphenylphosphonium iodide inthe presence of a base such as, but not limited to, potassiumt-butoxide, to provide alkenes of formulas (26) and (27) respectively,Reference for this method may be found in: Johnson Ylide Chemistry,Academic Press: New York, 1966, and Hopps, H. B., Biel, J. H.Aldrichimica Acta (1969), 2(2), 3-6 Alkenes of formulas (26) and (27)can be converted to alcohols of formulas (28) and (29) via a reactionsequence known as hydroboration-oxidation. Alcohols of formulas (28) and(29) can be treated with an agent such as, but not limited to, triflateanhydride, tosyl chloride, or mesyl chloride in the presence of a basesuch as, but not limited to, potassium carbonate, to provide thecorresponding triflate, tosylate, or mesylate respectively. Theresulting triflate, tosylate, or mesylate can be treated with an amineof formula (9), optionally in the presence of a base such as, but notlimited to, potassium carbonate or sodium carbonate, to provide aminesof formulas of (30) and (31) respectively. Compounds of formulas of (30)and (31) can be converted to amines of formulas (32) and (33)respectively using the reaction conditions described in Scheme 1.

Similarly, compounds of formulas (42) and (43), wherein R₃, R_(3a),R_(3b), R₄, and R₅ are as defined in formula (I); R₂ is-L₂-R_(6a)-L₃-R_(6b), and R₁ is hydrogen, alkyl, alkoxy, halogen, cyano,or thioalkoxy, wherein L₂ is a bond, —N(H), —N(alkyl), —O—, or —S—, andR_(6a), L₃, and R_(6b) are as defined in formula (I), can be prepared asdescribed in Scheme 4. Esters of formula (15) wherein R is a loweralkyl, X is Br, Cl, or I, can be converted to amines of formulas (42)and (43), using the reaction conditions as described in Scheme 3, exceptfor substituting boronic acid or esters of formula (12) for (23) andpinacol borane reagents of formula (12a) for (23a) for the Suzukireactions, and except for substituting organostannes of formula(R₁₀₂)₃SnR₂ for (R₁₀₂)₃SnR₁ for Stille coupling.

Compounds of formulas (46) and (47), wherein R₃, R_(3a), R_(3b), R₄, andR₅ are as defined in formula (I); R₂ is hydrogen, alkyl, alkoxy,halogen, cyano, or thioalkoxy; and R₁ is -L₂-R_(6a)-L₃-R_(6b), whereinL₂ is a bond, —N(H), —N(alkyl), —O—, or —S—, and R_(6a), L₃, and R_(6b)are as defined in formula (1), can be prepared as described in Scheme 5.Esters of formula (1) wherein R is a lower alkyl, X is Br, Cl, or I, canbe converted to alcohols of formulas (28) and (29) according Scheme 3.Alcohols of formulas (28) and (29) can be oxidized via a reaction knownas Swern oxidation, by an agent, such as, but not limited to, DMSO andoxalyl chloride in the presence of a base such as triethylamine toprovide aldehydes of formulas (44) and (45). Aldehydes of formulas (44)and (45) can be converted to amines of formulas (46) and (47)respectively using the reaction conditions described in Scheme 3transforming compounds of formulas (24) and (25) to compounds offormulas (32) and (33).

Similarly, compounds of formulas (50) and (51), wherein R₃, R_(3a),R_(3b), R₄, and R₅ are as defined in formula (1); R₁ is hydrogen, alkyl,alkoxy, halogen, cyano, or thioalkoxy, and R₂ is -L₂-R_(6a)-L₃-R_(6b),wherein L₂ is a bond, —N(H), —N(alkyl), —O—, or —S—, and R_(6a), L₃, andR_(6b) are as defined in formula (I), can be prepared as described inScheme 6, Esters of formula (15) wherein R is a lower alkyl, X is Br,Cl, or I, can be converted to alcohols of formulas (38) and (39) asdescribed in Scheme 4. Alcohols of formulas (38) and (39) can beoxidized via a reaction known as Swern oxidation, by an agent, such as,but not limited to, DMSO and oxalyl chloride to provide aldehydes offormulas (48) and (49) respectively, Aldehydes of formulas (48) and (49)can be converted to amines of formulas (50) and (51), respectively,using the reaction conditions described in Scheme 4 transformingcompounds of formulas (38) and (39) to compounds of formulas (42) and(43).

Esters of formula (1) wherein X is I, Br or Cl or hydroxy; R is a loweralkyl, R₃, R_(3a), and R_(3b) are as defined in formula (I); and R₂ ishydrogen, alkyl, alkoxy, halogen, cyano, or thioalkoxy; can be purchasedor prepared as described in Scheme 7. Halides of formula (52), wherein Yis I, Br, or triflate (prepared by the treatment of phenols withtriflate anhydride), can be treated with ethyl acrylate in the presenceof a palladium source such asdichlorobis(triphenylphosphine)palladium(II) (CAS #13965-03-2) ortris(dibenzylidineacetone)dipalladium (CAS #52409-22-0) or palladiumdiacetate, and a ligand such as tri(2-furyl)phosphine (CAS #5518-52-5)or triphenyl phosphine, in a solvent such as DMF at 25-150° C. toprovide the esters of formula (1).

Alternatively, esters of formula (1) can be prepared through substitutedbenzaldehydes of formula (53) via the Wittig reaction, which iswell-known to those skilled in the art of organic synthesis. Referencesthat describe these methods may be found in the following. S. Li et al.,Chemische Berichte, 123:1441-1442 (1990); T. Kauffmann et al.,Tetrahedron Lett., 22:5031-5034 (1981).

Similarly, esters of formula (15) wherein X is I, Br or Cl or hydroxy; Ris a lower alkyl; R₃, R_(3a), and R_(3b) are as defined in formula (1);and R₁ is hydrogen, alkyl, alkoxy, halogen, cyano, or thioalkoxy; can bepurchased or prepared as described in Scheme 7.

The compounds and intermediates of the invention may be isolated andpurified by methods well-known to those skilled in the art of organicsynthesis, Examples of conventional methods for isolating and purifyingcompounds can include, but are not limited to, chromatography on solidsupports such as silica gel, alumina, or silica derivatized withalkylsilane groups, by recrystallization at high or low temperature withan optional pretreatment with activated carbon, thin-layerchromatography, distillation at various pressures, sublimation undervacuum, and trituration, as described for instance in “Vogel's Textbookof Practical Organic Chemistry”, 5th edition (1989), by Furniss,Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical,Essex CM20 2JE, England.

The compounds of the invention have at least one basic nitrogen wherebya desired salt of the compound can be formed by treatment of thecompound with an acid. Examples of acids suitable for the reactioninclude, but are not limited to tartaric acid, lactic acid, succinicacid, as well as mandelic, atrolactic, methanesulfonic, ethanesulfonic,toluenesulfonic, naphthalenesulfonic, benzensulfonic, carbonic, fumaric,maleic, gluconic, acetic, propionic, salicylic, hydrochloric,hydrobromic, phosphoric, sulfuric, citric, or hydroxybutyric acid,camphorsulfonic, malic, phenylacetic, aspartic, glutamic, and the like

Compositions of the Invention

The invention also provides pharmaceutical compositions comprising atherapeutically effective amount of a compound of formula (I) incombination with a pharmaceutically acceptable carrier. The compositionscomprise compounds of the invention formulated together with one or morenon-toxic pharmaceutically acceptable carriers. The pharmaceuticalcompositions can be formulated for oral administration in solid orliquid form, for parenteral injection or for rectal administration.

The term “pharmaceutically acceptable carrier”, as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin, talc, cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil, safflower oil, sesameoil, olive oil, corn oil and soybean oil, glycols, such a propyleneglycol, esters such as ethyl oleate and ethyl laurate; agar; bufferingagents such as magnesium hydroxide and aluminum hydroxide, alginic acid;pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol,and phosphate buffer solutions, as well as other non-toxic compatiblelubricants such as sodium lauryl sulfate and magnesium stearate, as wellas coloring agents, releasing agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can alsobe present in the composition, according to the judgment of one skilledin the art of formulations.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally”, as used herein, refers to modes of administrationwhich include intravenous, intramuscular, intraperitoneal, intrasternal,subcutaneous, intraarticular injection and infusion

Pharmaceutical compositions for parenteral injection comprisepharmaceutically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions and sterile powders forreconstitution into sterile injectable solutions or dispersions Examplesof suitable aqueous and nonaqueous carriers, diluents, solvents orvehicles include water, ethanol, polyols (propylene glycol, polyethyleneglycol, glycerol, and the like, and suitable mixtures thereof),vegetable oils (such as olive oil) and injectable organic esters such asethyl oleate, or suitable mixtures thereof. Suitable fluidity of thecomposition may be maintained, for example, by the use of a coating suchas lecithin, by the maintenance of the required particle size in thecase of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservativeagents, wetting agents, emulsifying agents, and dispersing agents.Prevention of the action of microorganisms may be ensured by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, and the like. It may also bedesirable to include isotonic agents, for example, sugars, sodiumchloride and the like. Prolonged absorption of the injectablepharmaceutical form may be brought about by the use of agents delayingabsorption, for example, aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is oftendesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Suspensions, in addition to the active compounds, may contain suspendingagents, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.

If desired, and for more effective distribution, the compounds of theinvention can be incorporated into slow-release or targeted-deliverysystems such as polymer matrices, liposomes, and microspheres. They maybe sterilized, for example, by filtration through a bacteria-retainingfilter or by incorporation of sterilizing agents in the form of sterilesolid compositions, which may be dissolved in sterile water or someother sterile injectable medium immediately before use.

Injectable depot forms are made by forming microencapsulated matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled,Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations also are prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic, parenterally acceptablediluent or solvent such as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, one or morecompounds of the invention is mixed with at least one inertpharmaceutically acceptable carrier such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol, and salicylic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay; and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof. In the case of capsules, tablets and pills, the dosageform may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using lactose or milk sugar aswell as high molecular weight polyethylene glycols.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract in a delayedmanner. Examples of materials which can be useful for delaying releaseof the active agent can include polymeric substances and waxes.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers such as cocoa butter,polyethylene glycol or a suppository wax which are solid at ambienttemperature but liquid at body temperature and therefore melt in therectum or vaginal cavity and release the active compound.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches A desired compound ofthe invention is admixed under sterile conditions with apharmaceutically acceptable carrier and any needed preservatives orbuffers as may be required. Ophthalmic formulation, ear drops, eyeointments, powders and solutions are also contemplated as being withinthe scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, animal and vegetable fats, oils,waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, lactose, talc, silicic acid, aluminum hydroxide, calciumsilicates and polyamide powder, or mixtures of these substances. Sprayscan additionally contain customary propellants such aschlorofluorohydrocarbons.

Compounds of the invention may also be administered in the form ofliposomes. As is known in the art, liposomes are generally derived fromphospholipids or other lipid substances. Liposomes are formed by mono-or multi-lamellar hydrated liquid crystals that are dispersed in anaqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes may be used. Thepresent compositions in liposome form may contain, in addition to thecompounds of the invention, stabilizers, preservatives, and the like.The preferred lipids are the natural and synthetic phospholipids andphosphatidylcholines (lecithins) used separately or together.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y., (1976), p 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compound ismixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants, which canbe required. Opthalmic formulations, eye ointments, powders andsolutions are contemplated as being within the scope of this invention.Aqueous liquid compositions comprising compounds of the invention alsoare contemplated.

The compounds of the invention can be used in the form ofpharmaceutically acceptable salts, esters, or amides derived frominorganic or organic acids. The term “pharmaceutically acceptable salts,esters and amides”, as used herein, refer to carboxylate salts, aminoacid addition salts, zwitterions, esters and amides of compounds offormula (I) which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response, and the like, arecommensurate with a reasonable benefit/risk ratio, and are effective fortheir intended use.

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, and arecommensurate with a reasonable benefit/risk ratio, Pharmaceuticallyacceptable salts are well-known in the art. The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention or separately by reacting a free base function with a suitableorganic acid.

Representative acid addition salts include, but are not limited toacetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethansulfonate (isethionate), lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, phosphate, glutamate,bicarbonate, p-toluenesulfonate and undecanoate. Preferred salts of thecompounds of the invention are the tartrate and hydrochloride salts.

Examples of acids which can be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acidand such organic acids as oxalic acid, maleic acid, succinic acid, andcitric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as the hydroxide,carbonate or bicarbonate of a pharmaceutically acceptable metal cationor with ammonia or an organic primary, secondary or tertiary amine.Pharmaceutically acceptable salts include, but are not limited to,cations based on alkali metals or alkaline earth metals such as lithium,sodium, potassium, calcium, magnesium, and aluminum salts, and the like,and nontoxic quaternary ammonia and amine cations including ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine, diethylamine, ethylamine and the such as.Other representative organic amines useful for the formation of baseaddition salts include ethylenediamine, ethanolamine, diethanolamine,piperidine, and piperazine.

Also, the basic nitrogen-containing groups can be quaternized with suchagents as lower alkyl halides such as methyl, ethyl, propyl, and butylchlorides, bromides and iodides, dialkyl sulfates such as dimethyl,diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkylhalides such as benzyl and phenethyl bromides and others. Water oroil-soluble or dispersible products are thereby obtained.

The term “pharmaceutically acceptable ester”, as used herein, refers toesters of compounds of the invention which hydrolyze in vivo and includethose that break down readily in the human body to leave the parentcompound or a salt thereof. Examples of pharmaceutically acceptable,non-toxic esters of the invention include C₁-to-C₆ alkyl esters andC₅-to-C₇ cycloalkyl esters, although C₁-to-C₄ alkyl esters arepreferred. Esters of the compounds of formula (I) may be preparedaccording to conventional methods. For example, such esters may beappended onto hydroxy groups by reaction of the compound that containsthe hydroxy group with acid and an alkylcarboxylic acid such as aceticacid, or with acid and an arylcarboxylic acid such as benzoic acid. Inthe case of compounds containing carboxylic acid groups, thepharmaceutically acceptable esters are prepared from compoundscontaining the carboxylic acid groups by reaction of the compound withbase such as triethylamine and an alkyl halide, alkyl trifilate, forexample with methyliodide, benzyl iodide, cyclopentyl iodide. They alsomay be prepared by reaction of the compound containing the carboxylicacid group with an acid such as hydrochloric acid and an alcohol such asmethanol or ethanol.

The term “pharmaceutically acceptable amide”, as used herein, refers tonon-toxic amides of the invention derived from ammonia, primary C₁-to-C₆alkyl amines and secondary C₁-to-C₆ dialkyl amines. In the case ofsecondary amines, the amine may also be in the form of a 5- or6-membered heterocycle containing one nitrogen atom. Amides derived fromammonia, C₄-to-C₃ alkyl primary amides and C₁-to-C₂ dialkyl secondaryamides are preferred. Amides of the compounds of formula (I) may beprepared according to conventional methods. Pharmaceutically acceptableamides are prepared from compounds containing primary or secondary aminegroups by reaction of the compound that contains the amino group with analkyl anhydride, aryl anhydride, acyl halide, or aryl halide. In thecase of compounds containing carboxylic acid groups, thepharmaceutically acceptable esters are prepared from compoundscontaining the carboxylic acid groups by reaction of the compound withbase such as triethylamine, a dehydrating agent such as dicyclohexylcarbodiimide or carbonyl diimidazole, and an alkyl amine, dialkylamine,for example with methylamine, diethylamine, piperidine. They also may beprepared by reaction of the compound with an acid such as sulfuric acidand an alkylcarboxylic acid such as acetic acid, or with acid and anarylcarboxylic acid such as benzoic acid under dehydrating conditions aswith molecular sieves added. The composition can contain a compound ofthe invention in the form of a pharmaceutically acceptable prodrug.

The term “pharmaceutically acceptable prodrug” or “prodrug”, as usedherein, represents those prodrugs of the compounds of the inventionwhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use.Prodrugs of the invention may be rapidly transformed in vivo to a parentcompound of formula (I), for example, by hydrolysis in blood. A thoroughdiscussion is provided in T. Higuchi and V. Stella, Pro-drugs as NovelDelivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B,Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press (1987), herebyincorporated by reference

The invention contemplates pharmaceutically active compounds eitherchemically synthesized or formed by in viva biotransformation tocompounds of formula (I).

Methods of the Invention

The compounds and compositions of the invention are useful for treatingand preventing certain diseases and disorders in humans and animals. Asan important consequence of the ability of the compounds of theinvention to modulate the effects of histamine-3 receptors in cells, thecompounds described in the invention can affect physiological processesin humans and animals. In this way, the compounds and compositionsdescribed in the invention are useful for treating and preventingdiseases and disorders modulated by histamine-3 receptors. Typically,treatment or prevention of such diseases and disorders can be effectedby selectively modulating the histamine-3 receptors in a mammal, byadministering a compound or composition of the invention, either aloneor in combination with another active agent as part of a therapeuticregimen.

The compounds of the invention, including but not limited to thosespecified in the examples, possess an affinity for the histamine-3receptors and therefore, the compounds of the invention may be usefulfor the treatment and prevention of diseases or conditions such asattention-deficit hyperactivity disorder (ADHD), deficits in attention,dementia, and diseases with deficits of memory, learning, schizophrenia,cognitive deficits of schizophrenia, cognitive deficits and dysfunctionin psychiatric disorders, Alzheimer's disease, mild cognitiveimpairment, epilepsy, seizures, allergic rhinitis, and asthma, motionsickness, dizziness, Meniere's disease, vestibular disorders, vertigo,obesity, diabetes, type II diabetes, Syndrome X, insulin resistancesyndrome, metabolic syndrome, pain, including neuropathic pain,neuropathy, sleep disorders, narcolepsy, pathological sleepiness, jetlag, drug abuse, mood alteration, bipolar disorder, depression,obsessive compulsive disorder, Tourette's syndrome, Parkinson's disease,and medullary thyroid carcinoma, melanoma, and polycystic ovarysyndrome. The ability of histamine-3 receptor modulators, andconsequently the compounds of the invention, to prevent or treat suchdisorders is demonstrated by examples found in the following references.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat attention-deficithyperactivity disorder (ADHD), and deficits in attention, may bedemonstrated by Cowart, et al. J. Med. Chem. 2005, 48, 38-55; Fox, G.B., et al “Pharmacological Properties of ABT-239, II. NeurophysiologicalCharacterization and Broad Preclinical Efficacy in Cognition andSchizophrenia of a Potent and Selective Histamine H₃ ReceptorAntagonist”, Journal of Pharmacology and Experimental Therapeutics(2005) 313, 176-190; “Effects of histamine H₃ receptor ligands GT-2331and ciproxifan in a repeated acquisition avoidance response in thespontaneously hypertensive rat pup.” Fox, G. B., et al. BehaviouralBrain Research (2002), 131(1,2), 151-161; Yates, et al. JPET (1999) 289,1151-1159 “identification and Pharmacological Characterization of aSeries of New 1H-4-Substituted-Imidazoyl Histamine H₃ Receptor Ligands”,Ligneau, et al. Journal of Pharmacology and Experimental Therapeutics(1998), 287, 658-666, Tozer, M. Expert Opinion Therapeutic Patents(2000) 10, 1045; M. T Halpern, “GT-2331” Current Opinion in Central andPeripheral Nervous System Investigational Drugs (1999) 1, 524-527;Shaywitz et al., Psychopharmacology, 82.73-77 (1984); Dumery andBlozovski, Exp. Brain Res., 67:61-69 (1987); Tedford et al., J.Pharmacol. Exp. Ther., 275:598-604 (1995); Tedford et al., Soc.Neurosci. Abstr., 22:22 (1996); and Fox, et al., Behav. Brain Res.,131:151-161 (2002); Glase, S. A., et al. “Attention deficithyperactivity disorder: pathophysiology and design of new treatments”Annual Reports in Medicinal Chemistry (2002), 37 11-20; Schweitzer, J.B., and Holcomb, H. H. “Drugs Linder investigation for attention-deficithyperactivity disorder” Current Opinion in Investigative Drugs (2002) 3,1207.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat dementia, anddiseases with deficits of memory and learning, may be demonstrated by“Two novel and selective nonimidazole H₃ receptor antagonists A-304121and A-317920: II. In vivo behavioral and neurophysiologicalcharacterization.” Fox, G. B., et al. Journal of pharmacology andexperimental therapeutics (2003 June), 305(3), 897-908, “Identificationof novel H₃ receptor (H₃R) antagonist with cognition enhancingproperties in rats.” It Fox, G. B.; Inflammation Research (2003),52(Suppl. 1), S31-S32; Bernaerts, P., et al. “Histamine H₃ antagonistthioperamide dose-dependently enhances memory consolidation and reversesamnesia induced by dizocilpine or scopolamine in a one-trial inhibitoryavoidance task in mice” Behavioural Brain Research 154 (2004) 211-219;Onodera, et al. Nauyn-Schmiedebergs' Arch. Pharmacol. (1998), 357,508-513; Prast, et al. Brain Research (1996) 734, 316-318, Chen, et al.Brain Research (1999) 839, 186-189 “Effects of histamine onMK-801-induced memory deficits in radial maze performance in rats”;Passani, et al. “Central histaminergic system and cognition”Neuroscience and Biobehavioral Reviews (2000) 24, 107-113.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat schizophrenia,cognitive deficits of schizophrenia, and cognitive deficits, may bedemonstrated by Fox, G. B., et al “Pharmacological Properties ofABT-239: II. Neurophysiological Characterization and Broad PreclinicalEfficacy in Cognition and Schizophrenia of a Potent and SelectiveHistamine H₃ Receptor Antagonist”, Journal of Pharmacology andExperimental Therapeutics (2005) 313, 176-190 and by II Enhancement ofprepulse inhibition of startle in mice by the H₃ receptor antagoniststhioperamide and ciproxifan Browman, Kaitlin E., et al. BehaviouralBrain Research (2004), 153(1), 69-76, “H₃ receptor blockade bythioperamide enhances cognition in rats without inducing locomotorsensitization.”, Komater, V. A., et al. Psychopharmacology (Berlin,Germany) (2003), 167(4), 363-372; A A Rodrigues, F P Jansen, R Leurs, HTimmerman and G D Prell “Interaction of clozapine with the histamine H₃receptor in rat brain” British Journal of Pharmacology (1995), 114(8),pp. 1523-1524, Passani, et al. “Central histaminergic system andcognition” Neuroscience and Biobehavioral Reviews (2000) 24, 107-113;Morriset, S., et al. “Atypical Neuroleptics Enhance Histamine Turnoverin Brain Via 5-Hydroxytryptamine_(2A) Receptor Blockade” Journal ofPharmacology and Experimental Therapeutics (1999) 288, 590-596.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat dysfunction inpsychiatric disorders, Alzheimer's disease, and mild cognitiveimpairment may be demonstrated by Meguro, et al. Pharmacology,Biochemistry and Behavior (1995) 50(3), 321-325; Esbenshade, T., et al.“Pharmacological and behavioral properties of A-349821, a selective andpotent human histamine H3 receptor antagonist” Biochemical Pharmacology68 (2004) 933-945; Huang, Y.-W., et al. “Effect of the histamineH3-antagonist clobenpropit on spatial memory deficits induced by MK-801as evaluated by radial maze in Sprague-Dawley rats” Behavioural BrainResearch 151 (2004) 287-293; Mazurkiewicz-Kwilecki and Nsonwah, Can. J.Physiol. Pharmacol. (1989) 67, 75-78; P. Panula, et al., Neuroscience(1997) 82, 993-997; Haas, et al., Behav. Brain Res. (1995) 66, 41-44; DeAlmeida and Izquierdo, Arch, Int. Pharmacodyn. (1986), 283, 193-198;Kamei et al., Psychopharmacology, (1990) 102, p 312-318; Kamei andSakata, Jpn. J. Pharmacol (1991), 57, 437-482; Schwartz et al.,Psychopharmacology, The Fourth Generation of Progress Bloom and Kupfer(eds). Raven Press, New York, (1995) 397, and Wada, et al., Trends inNeurosci. (1991) 14, p. 415.

The ability of the compounds of the invention, including, but notlimited to, is those specified in the examples, to treat epilepsy, andseizures, may be demonstrated by Harada, C., et al. “Inhibitory effectof iodophenpropit, a selective histamine H3 antagonist, on amygdaloidkindled seizures” Brain Research Bulletin (2004) 63: 143-146, as well asby Yokoyama, et al., Eur. J. Pharmacol (1993) 234:129-133; Yokoyama, etal. European Journal of Pharmacology (1994) 260; 23; Yokoyama andIinuma, CNS Drugs (1996) 5:321; Vohora, Life Sciences (2000) 66:297-301; Onodera et al., Prog. Neurobiol. (1994) 42: 685, Chen, Z., etal. “Pharmacological effects of carcinine on histaminergic neurons inthe brain” British Journal of Pharmacology (2004) 143, 573-580; R Leurs,R. C. Vollinga and H. Timmerman, “The medicinal chemistry andtherapeutic potential of ligands of the histamine H₃ receptor”, Progressin Drug Research (1995) 45; 170-165; Leurs and Timmerman, Prog. DrugRes. (1992) 39: 127, H. Yokoyama and K. Iinuma, “Histamine and Seizures:Implications for the treatment of epilepsy”, CNS Drugs, 5(5); 321-330(1995); and K. Hurukami, H. Yokoyama, K, Onodera, K. Iinuma and T.Watanabe, “AQ-0145, A newly developed histamine H₃ antagonist, decreasedseizure susceptibility of electrically induced convulsions in mice”,Meth Find. Exp. Clin. Pharmacol., 17(C):70-73 (1995); Yawata, et al.“Role of histaminergic neurons in development of epileptic seizures inEL mice” Molecular Brain Research 132 (2004) 13-17.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat allergic rhinitis,and asthma, may be demonstrated by McLeod, R. L., Mingo, G. G., Herczku,C., DeGennaro-Culver, F., Kreutner, W., Egan, R. W., Hey, J. A.,“Combined histamine H1 and H3 receptor blockade produces nasaldecongestion in an experimental model of nasal congestion” Am. J.Rhinol. (1999a) 13, 391-399; McLeod, Robbie L.; Egan, Robert W.; Cuss,Francis M.; Bolser, Donald C., Hey, John A. (Allergy, Schering-PloughResearch Institute, Kenilworth, N.J., USA.) Progress in RespiratoryResearch (2001), 31 (in New Drugs for Asthma, Allergy and COPD):133-136; A. Delaunois A., et al., “Modulation of acetylcholine,capsaicin and substance P effects by histamine H₃ receptors in isolatedperfused rabbit lungs,” European Journal of Pharmacology (1995) 277:243-250; Dimitriadou, et al., “Functional relationship between mastcells and C-sensitive nerve fibres evidenced by histamine H₃-receptormodulation in rat lung and spleen,” Clinical Science (1994), 87:151-163

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat motion sickness,dizziness, Meniere's disease, vestibular disorders, and vertigo, may bedemonstrated by Pan, et al. Methods and Findings in ClinicalPharmacology (1998), 20(9), 771-777; O'Neill, et al. Methods andFindings in Clinical Pharmacology (1999) 21(4), 285-289; and by R.Leurs, R. C. Vollinga and H. Timmerman, “The medicinal chemistry andtherapeutic potential of ligands of the histamine H₃ receptor,” Progressin Drug Research (1995), 45: 170-165, Lozada, et al. “Plasticity ofhistamine H₃ receptor expression and binding in the vestibular nucleiafter labyrinthectomy in rat” BioMedCentral Neuroscience 2004, 5:32.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat obesity, diabetes,type II diabetes, Syndrome X, insulin resistance syndrome, and metabolicsyndrome, may be demonstrated by Hancock, A. A. “Antiobesity effects ofA-331440, a novel non-imidazole histamine H3 receptor antagonist”European Journal of Pharmacology (2004) 487, 183-197; Hancock, A. A., etal. “Histamine H₃ antagonists in models of obesity” Inflamm. res. (2004)53, Supplement 1 S47-S48, as well as by E. Itoh, M. Fujimiay, and A.Inui, “Thioperamide, A histamine H₃ receptor antagonist, powerfullysuppresses peptide YY-induced food intake in rats,” Biol. Psych. (1999)45(4): 475-481; S. I. Yates, et al., “Effects of a novel histamine H₃receptor antagonist, GT-2394, on food intake and weight gain inSprague-Dawley rats,” Abstracts, Society for Neuroscience, 102 10:219(November, 2000); and C. Bjenning, et al., “Peripherally administeredciproxifan elevates hypothalamic histamine levels and potently reducesfood intake in the Sprague Dawley rat,” Abstracts, International SendaiHistamine Symposium, Sendai, Japan, #P39 (November, 2000); Sakata T; etal. “Hypothalamic neuronal histamine modulates ad libitum feeding byrats,” Brain research (1990 Dec. 24), 537(1-2), 303-6.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat pain, includingneuropathic pain and neuropathy, may be demonstrated by Malmberg-Aiello,Petra; Lamberti, Claudia; Ghelardini, Carla; Giotti, Alberto, Bartolini,Alessandro. British Journal of Pharmacology (1994), 111(4), 1269-1279;Hriscu, Anisoara; Gherase, Florenta, Pavelescu, M., Hriscu, En“Experimental evaluation of the analgesic efficacy of someantihistamines as proof of the histaminergic receptor involvement inpain.” Farmacia, (2001), 49(2), 23-30, 76.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat sleep disorders,including narcolepsy and pathological sleepiness, and jet lag, may bedemonstrated by Barbier, A. J., et al. “Acute wake-promoting actions ofJNJ-5207852, a novel, diamine-based H₃ antagonist” British Journal ofPharmacology (2004) 1-13; Monti et al., Neuropsychopharmacology (1996)15, 31-35, Lin et al., Brain Res. (1990) 523; 325-330; Monti, et al.,Neuropsychopharmacology (1996) 15<31-35; Ligneau, et al. Journal ofPharmacology and Experimental Therapeutics (1998), 287, 658-666; Sakai,et al., Life Sci. (1991) 48; 2397-2404; Mazurkiewicz-Kwilecki andNsonwah, Can J. Physiol. Pharmacol., (1989) 67: 75-78, P. Panula, etal., Neuroscience (1998) 44, 465-481; Wada, et al., Trends inNeuroscience (1991) 14: 415; and Monti, et al., Eur. J. Pharmacol.(1991), 205; 283, Dvorak, C., et al. “4-Phenoxypiperidines: Potent,Conformationally Restricted, Non-Imidazole Histamine H₃ Antagonists”Journal of Medicinal Chemistry (2005) 48, 2229-2238.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat drug abuse.Amphetamine is an abused stimulant in humans. It, and similar abuseddrugs stimulate locomotor activity in animals, and it has been foundthat the H₃ antagonist thioperamide suppresses the locomotor stimulationinduced by amphetamine, therefore H₃ antagonists are likely to be usefulfor treating drug abuse as may be demonstrated by Clapham J.; KilpatrickG. J. “Thioperamide, the selective histamine H₃ receptor antagonist,attenuates stimulant-induced locomotor activity in the mouse”, Europeanjournal of pharmacology (1994), 259(2), 107-14.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat mood alteration,bipolar disorder, depression, obsessive compulsive disorder, andTourette's syndrome, may be demonstrated by Lamberti, et al. BritishJournal of Pharmacology (1998) 123, 1331-1336; Perez-Garcia C, et. al.,Psychopharmacology (Berlin) (1999) 142(2); 215-20.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat Parkinson'sdisease (a disease wherein patients have deficits in ability to initiatemovements, and patients' brain have low dopamine levels) may bedemonstrated by Sánchez-Lemus, E., et al. “Histamine H₃ receptoractivation inhibits dopamine D₁ receptor-induced cAMP accumulation inrat striatal slices” Neuroscience Letters (2004) 364, p. 179-184; Sakai,et al., Life Sci. (1991) 48, 2397-2404; Fox, G. B., et al.“Pharmacological Properties of ABT-239: II. NeurophysiologicalCharacterization and Broad Preclinical Efficacy in Cognition andSchizophrenia of a Potent and Selective Histamine H₃ ReceptorAntagonist” Journal of Pharmacology and Experimental Therapeutics,313:176-190, 2005; Chen, Z., et al. “Pharmacological effects ofcarcinine on histaminergic neurons in the brain” British Journal ofPharmacology (2004) 143, 573-580.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat medullary thyroidcarcinoma, melanoma, polycystic ovary syndrome, may be demonstrated byPolish Med. Sci. Mon (1998) 4(5): 747, Adam Szelag, “Role of histamineH₃-receptors in the proliferation of neoplastic cells in vitro,” Med.Sci Monitor (1998) 4(5):747-755, and C. H. Fitzsimons, et al.,“Histamine receptors signalling in epidermal tumor cell lines with H-rasgene alterations,” Inflammation Res. (1998) 47 (Suppl 1)₅S50-S51.

Compounds of the invention are particularly useful for treating andpreventing a condition or disorder affecting attention-deficithyperactivity, Alzheimer's disease, or dementia. Compounds of theinvention are particularly useful for treating and preventing acondition or disorder affecting schizophrenia or cognitive deficits ofschizophrenia. Compounds of the invention are particularly useful fortreating and preventing a condition or disorder affecting narcolepsy,sleep disorders, allergic rhinitis, asthma, or obesity.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s) that is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved.

When used in the above or other treatments, a therapeutically effectiveamount of one of the compounds of the invention can be employed in pureform or, where such forms exist, in pharmaceutically acceptable salt,ester, amide or prodrug form. Alternatively, the compound can beadministered as a pharmaceutical composition containing the compound ofinterest in combination with one or more pharmaceutically acceptablecarriers. The phrase “therapeutically effective amount” of the compoundof the invention means a sufficient amount of the compound to treatdisorders, at a reasonable benefit/risk ratio applicable to any medicaltreatment. It will be understood, however, that the total daily usage ofthe compounds and compositions of the invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific therapeutically effective dose level for any particular patientwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment, drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. For example, it is wellwithin the skill of the art to start doses of the compound at levelslower than required to achieve the desired therapeutic effect and togradually increase the dosage until the desired effect is achieved.

For treatment or prevention of disease, the total daily dose of thecompounds of this invention administered to a human or lower animal mayrange from about 0.001 to about 30 mg/kg of body weight. For purposes oforal administration, more preferable doses can be in the range of fromabout 0.001 to about 1 mg/kg body weight. If desired, the effectivedaily dose can be divided into multiple doses for purposes ofadministration; consequently, single dose compositions may contain suchamounts or submultiples thereof to make up the daily dose.

The compounds and processes of the invention will be better understoodby reference to the following examples, which are intended as anillustration of and not a limitation upon the scope of the invention.

EXAMPLES Example 14′-((1S,2S)-2-{[(2S)-2-Methylpyrrolidin-1-yl]methyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrileExample 1A trans-3-(4-Bromophenyl) prop-2-en-1-ol

To a solution of ethyl trans-4-bromocinnamate (8 mL, 42.6 mmol) inanhydrous dichloromethane (150 mL) under N₂ was added diisobutylaluminumhydride in dichloromethane (128 mL, 1M, 128 mmol) at −78° C. dropwise.After the addition, the mixture was allowed to warm from −78° C. to −30°C. over two hours. The mixture was then cooled back to −78° C. andaqueous 1 N HCl was added till acidic (pH=2). The organic layer wasseparated and the aqueous layer was extracted with dichloromethane. Thecombined organic layers were dried with MgSO₄, filtered and concentratedunder reduced pressure to provide the title compound ¹H NMR (300 MHz,CDCl₃):

1.44 (t, J=6 Hz, 1H), 4.32 (t, J=4.5 Hz, 2H), 6.37 (dt, J=16.5 Hz, J=6Hz, 1H), 6.57 (dt, J=15 Hz, J=3 Hz, 1H), 7.25 (d, J=9 Hz, 2H), 7.45 (d,J=9 Hz, 2H). MS (DCl—NH₃) m/z 214 (M+H)+.

Example 1B (1S,2S)-[2-(4-Bromophenyl)cyclopropyl]methanol

The title compound was prepared by the method of A. B. Charette and H.Lebel (Organic Synthesis, 1998, 76, 86-96) substitutingtrans-3-(4-bromophenyl) prop-2-en-1-ol (the product of Example 1A) for3-phenyl-prop-2-en-1-ol. ¹H NMR (300 MHz, CDCl₃): δ 0.92-1.0 (m, 2H),1.45-1.48 (m, 2H), 1.76-1.85 (m, 1H), 3.61 (d, J=7.5 Hz, 2H), 6.95 (d,J=9 Hz, 2H), 7.37 (d, J=9 Hz, 2H). MS (DCl—NH₃) m/z 228 (M+H)⁺.

Example 1C (1S,2S)-2-(4-Bromophenyl)cyclopropanecarbaldehyde

DMSO (0.8 mL, 3 equivalents) was added dropwise to a solution of oxalylchloride (0.48 mL) in anhydrous dichloromethane (50 mL) under N₂ at −78°C. A solution of (1S,2S)-[2-(4-bromophenyl)cyclopropyl]methanol (theproduct from Example 1B, 823 mg) in dichloromethane (20 mL) was thenadded dropwise at −78° C. Stirring at this temperature was continued for30 minutes, then triethylamine (2 mL, 4 equivalents) was added, and thedry ice bath was removed. After stirring for 1 hour, the mixture wastreated with saturated aqueous NH₄Cl. The mixture was extracted withdiethyl ether twice. The combined organic extracts were dried (MgSO₄)and filtered. The filtrate was concentrated under reduced pressure. Theresidue was purified by elution through a pad of silica gel with hexaneto provide the title compound. ¹H NMR (300 MHz, CDC₃): δ 1.48 (m, 1H),1.65 (dt, J=9 Hz, J=6 Hz, 1H), 2.15 (m, 1H), 2.57 (m, 1H), 6.98 (d, J=9Hz, 2H), 7.45 (d, J=9 Hz, 2H), 9.46 (d, J=4.5 Hz, 1H). MS (DCl—NH₃) m/z226 (M+H)+.

Example 1D1-[(1S,2S)-2-(4-Bromo-phenyl)-cyclopropylmethyl]-2(S)-methyl-pyrrolidine

A solution of (1S,2S)-2-(4-bromophenyl)cyclopropanecarbaldehyde (theproduct of Example 1C, 820 mg, 3.64 mmol) and (S)-2-methylpyrrolidinetartaric acid salt (1.12 g, 4.73 mmol) in ethanol (30 mL) was treatedwith sodium cyanoborohydride (345 mg 5.46 mmol). The mixture was stirredat room temperature for two hours. The mixture was basified to pH=10-12with NaOH (10%) and partitioned between ethyl acetate and water. Theaqueous layer was extracted with ethyl acetate (2×). The combinedorganic layers were dried (MgSO₄) and filtered. The filtrate wasconcentrated under reduced pressure and the residue was purified onsilica gel eluting with 1% to 2% methanol (containing 10% concentratedNH₄OH) in dichloromethane to provide the title compound. ¹H NMR (300MHz, CDCl₃):

0.87-0.92 (m, 1H), 0.97-1.02 (m, 1H), 1.16 (d, J=6 Hz, 2H), 1.22 (m,1H), 1.39-1.49 (m, 1H), 1.73-1.81 (m, 3H), 2.0 (m, 2H), 2.36 (q, J=6 Hz,1H), 2.45 (m, 1H), 3.13 (dd, J=12 Hz, J=6 Hz, 1H), 3.25 (m, 1H), 7.00(d, J=6 Hz, 2H), 7.37 (d, J=6 Hz, 2H). MS (DCl—NH₃) m/z 294 (M+H)⁺.

(S)-2-methylpyrrolidine and its salts are available commercially from anumber of sources including; (S)-2-methylpyrrolidine (Chemical abstractsregistry number 59335-84-1) from Sigma-Aldrich Chemical Company, P. O.Box 14508 St Louis, Mo., 63178 USA, and (S)-2-methylpyrrolidinehydrochloride (Chemical abstracts registry number 174500-74-4) fromAstaTech, Inc. Keystone Business Park 2525 Pearl Buck Road Bristol, Pa.,19007 USA. Methods of obtaining (S)-2-methylpyrrolidine byenantioselective recrystallization with tartaric acid have beendescribed for example in Sakurai, et al. Crystal Growth & Design (2006)vol. 6(7) pages 1606-1610, (S)-2-Methylpyrrolidine L-tartaric acid salt(313 grams) was recrystallized from a mixture of 4.8 Liters of ethanoland 1.2 liters of methanol heated at 60° C. and allowed to cool todeposit (S)-2-methylpyrrolidine L-tartaric acid salt.

Example 1E4′-((1S,2S)-2-{[(2S)-2-Methylpyrrolidin-1-yl]methyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrile

To a solution of1-[(1S,2S)-2-(4-bromo-phenyl)-cyclopropylmethyl]-2(S)-methyl-pyrrolidine(the product of Example 1D, 50 mg, 0.17 mmol) in isopropyl alcohol (4mL) under an atmosphere of nitrogen was added 4-cyanophenylboronic acid(30 mg, 0.2 mmol), dichlorobis(triphenylphosphine)palladium(II) (6 mg,8.5 μmol) and potassium carbonate (59 mg, 0.43 mmol). The mixture washeated to 90° C. for 5 hours, cooled to ambient temperature andpartitioned between ethyl acetate (25 mL) and H₂O (10 mL). The separatedorganic layer was washed with brine, dried (MgSO₄), filtered,concentrated under reduced pressure and chromatographed on silica geleluting with 3% methanol (containing 10% concentrated NH₄OH) indichloromethane to provide the title compound ¹H NMR (300 MHz, CD₃OD)

1.01 (m, 1H), 1.13 (m, 1H), 1.25 (d, J=6 Hz, 3H), 1.36 (m, 1H), 1.54 (m,1H), 1.89 (m, 3H), 2.11 (m, 1H), 2.30 (m, 1H), 2.65 (m, 1H), 2.79 (m,1H), 3.27 (dd J=12 Hz, J=6 Hz, 1H), 3.40 (m, 1H), 7.22 (d, J=9 Hz, 2H),7.59 (d, J=6 Hz, 2H), 7.78 (s, 4H). MS (DCl—NH₃) m/z 317 (M+H)⁺.

Example 24′-((1S,2S)-2-{[(2R)-2-Methylpyrrolidin-1-yl]methyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrileExample 2A1-[2-(4-Bromo-phenyl)-(1S,2S)-cyclopropylmethyl]-(2R)-2-methyl-pyrrolidine

The title compound was prepared using the procedure described in Example1D, substituting (R)-2-methylpyrrolidine for (S)-2-methylpyrrolidine ¹HNMR (300 MHz, CD₃OD);

0.92 (m, 1H), 0.99 (m, 1H), 1.13 (d, J=6 Hz, 3H), 1.24 (m, 1H), 1.43 (m,1H), 1.77 (m, 3H), 1.98 (m, 2H), 2.13 (dd, J=12 Hz, J=6 Hz, 1H), 2.30(q, J=9 Hz, 1H), 241 (m, 1H), 2.94 (dd, J=12 Hz, J=6 Hz, 1H), 3.25 (m,1H), 7.00 (d, J=9 Hz, 2H), 7.36 (d, J=9 Hz, 2H) MS (DCl—NH₃) m/z 294(M+H)⁺.

(R)-2-methylpyrrolidine and its salts are available commercially from anumber of sources, including, (R)-2-methylpyrrolidine (Chemicalabstracts registry number 41720-98-3) from Sigma-Aldrich ChemicalCompany, P.O. Box 14508 St. Louis, Mo., 63178 USA, and(R)-2-methylpyrrolidine hydrochloride (Chemical abstracts registrynumber 135324-85-5) from AstaTech, Inc. Keystone Business Park 2525Pearl Buck Road Bristol, Pa., 19007 USA. Methods of obtaining(R)-2-methylpyrrolidine by enantioselective recrystallization withtartaric acid have been described for example in Sakurai, et al. CrystalGrowth & Design (2006) vol. 6(7) pages 1606-1610 and in Pu, et al.Organic Process Research & Development 2005, 9, 45-50.

Example 2B4′-((1S,2S)-2-{[(2R)-2-Methylpyrrolidin-1-yl]methyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrile

The title compound was prepared using the procedure described in Example1E substituting1-[2-(4-bromo-phenyl)-(1S,2S)-cyclopropylmethyl]-(2R)-2-methyl-pyrrolidine(the product from Example 2A) for1-[(1S,2S)-2-(4-bromo-phenyl)-cyclopropylmethyl]-2(S)-methyl-pyrrolidine(the product from 1D). ¹H NMR (300 MHz, CD₃OD):

0.92 (m, 1H), 0.99 (m, 1H), 1.13 (d, J=6 Hz, 2H), 1.24 (m, 1H), 1.43 (m,1H), 1.77 (m, 3H), 1.98 (m, 2H), 2.13 (dd, J=12 Hz, J=6 Hz, 1H), 2.30(q, J=9 Hz, 1H), 2.41 (m, 1H), 2.94 (dd, J=12 Hz, J=6 Hz, 1H), 3.25 (m,1H), 7.00 (d, J=9 Hz, 2H), 7.36 (d, J=9 Hz, 2H) MS (DCl—NH₃) m/z 294(M+H)⁺.

Example 34′-((1R,2R)-2-{[(2R)-2-Methylpyrrolidin-1-yl]methyl}cyclopropyl)-1′-biphenyl-4-carbonitrileExample 3A (1R,2R)-[2-(4-Bromophenyl)cyclopropyl]methanol

The title compound was prepared by the method of A. B. Charette and H.Lebel (Organic Synthesis, 1998, 76, 86-96) substitutingtrans-3-(4-Bromophenyl) prop-2-en-1-ol (the product from Example 1A) for3-Phenyl-prop-2-en-1-ol. ¹H NMR (300 MHz, CDCl₃): δ 0.92-1.0 (m, 2H),1.45-1.48 (m, 2H), 1.76-1.85 (m, 1H), 3.61 (d, J=7.5 Hz, 2H), 6.95 (d,J=9 Hz, 2H), 7.37 (d, J=9 Hz, 2H). MS (DCl—NH₃) m/z 228 (M+H)⁺.

Example 3B (1R,2R)-2-(4-Bromophenyl)cyclopropanecarbaldehyde

DMSO (0.8 mL, 3 equivalents) was added dropwise to a solution of oxalylchloride (0.48 mL) in anhydrous dichloromethane (50 mL) under N₂ at −78°C. A solution of (1R,2R)-[2-(4-bromophenyl)cyclopropyl]methanol (theproduct of Example 3A, 823 mg) in dichloromethane (20 mL) was then addeddropwise at −78° C. Stirring at this temperature was continued for 30minutes, then triethylamine (2 mL, 4 equivalents) was added and the dryice bath was removed. After stirring for 1 hour, the mixture was treatedwith saturated aqueous NH₄Cl. The mixture was extracted with diethylether. The combined organic extracts were dried (MgSO₄) and filtered.The filtrate was concentrated under reduced pressure. The residue waspurified by elution through a pad of silica gel with hexane to providethe title compound. ¹H NMR (300 MHz, CDCl₃): δ 1.48 (m, 1H), 1.65 (dt,J=9 Hz, J=6 Hz, 1H), 2.15 (m, 1H), 2.57 (m, 1H), 6.98 (d, J=9 Hz, 2H),7.45 (d, J=9 Hz, 2H), 9.46 (d, J=4.5 Hz, 1H). MS (DCl—NH₃) m/z 226(M+H)⁺.

Example 3C1-[2-(4-Bromo-phenyl)-(1R,2R)-cyclopropylmethyl]-(2R)-2-methyl-pyrrolidine

A solution of (1R,2R)-2-(4-bromophenyl)cyclopropanecarbaldehyde (theproduct of Example 3B, 600 mg, 2.67 mmol) and (R)-2-methylpyrrolidinetartaric acid salt (0.82 g, 3.47 mmol) in ethanol (30 mL) was treatedwith sodium cyanoborohydride (252 mg 4 mmol). The mixture was stirred atroom temperature for two hours. The mixture was quenched with HCl (1N)and then basified to pH=10-12 with NaOH (10%) and partitioned betweenethyl acetate and water. The aqueous layer was extracted with ethylacetate. The combined organic layers were dried (MgSO₄) and filtered.The filtrate was concentrated under reduced pressure and the residue waspurified on silica gel with 1% to 2% methanol (containing 10%concentrated NH₄OH) in dichloromethane to provide the title compound. ¹HNMR (300 MHz, CD₃OD):

0.89 (m, 1H), 0.98 (m, 1H), 1.14 (d, J=6 Hz, 2H), 1.19 (m, 1H), 1.43 (m,1H), 1.75 (m, 3H), 1.95 (m, 2H), 2.30 (q, J=9 Hz, 1H), 2.37 (m, 1H),3.14 (dd, J=12 Hz, J=6 Hz, 1H), 3.22 (m, 1H), 7.00 (d, J=9 Hz, 2H), 7.36(d, J=9 Hz, 2H). MS (DCl—NH₃) m/z 294 (M+H)⁺.

Example 3D4′-((1R,2R)-2-{[(2R)-2-Methylpyrrolidin-1-yl]methyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrile

To a solution of1-[2-(4-bromo-phenyl)-(1R,2R)-cyclopropylmethyl]-(2R)-2-methyl-pyrrolidine(product of Example 3C, 50 mg, 0.17 mmol) in isopropyl alcohol (4 mL)under an atmosphere of nitrogen was added 4-cyanophenylboronic acid (30mg, 0.2 mmol), dichlorobis(triphenylphosphine)palladium(II) (6 mg, 8.5μmol) and potassium carbonate (59 mg, 0.43 mmol). The mixture was heatedto 90° C. for 5 hours, cooled to ambient temperature and partitionedbetween ethyl acetate (25 mL) and H₂O (10 mL). The organic extractionwas washed with brine, dried (MgSO₄), filtered, concentrated underreduced pressure and chromatographed on silica gel eluting with methanol(containing 10% concentrated NH₄OH) in dichloromethane to provide thetitle compound ¹H NMR (300 MHz, CD₃OD)

1.08 (m, 1H), 1.19 (m, 1H), 1.32 (d, J=6 Hz, 3H), 1.42 (m, 1H), 1.63 (m,1H), 1.99 (m, 3H), 2.20 (m, 1H), 2.65 (m, 1H), 2.94 (m, 1H), 3.07 (m,1H), 3.34 (dd, J=9 Hz, J=6 Hz, 1H), 3.51 (m, 1H), 7.24 (d, J=9 Hz, 2H),7.60 (d, J=6 Hz, 2H), 7.78 (s, 4H). MS (DCl—NH₃) m/z 317 (M+H)⁺.

Example 44′-((1R,2R)-2-{[(2S)-2-Methylpyrrolidin-1-yl]methyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrileExample 4A1-[2-(4-Bromo-phenyl)-(1R,2R)-cyclopropylmethyl]-(2S)-2-methyl-pyrrolidine

The title compound was prepared using the procedure described in Example3C substituting (S)-2-methylpyrrolidine tartaric acid salt for(R)-2-methylpyrrolidine tartaric acid salt. ¹H NMR (300 MHz, CD₃OD):

0.93 (m, 1H), 0.99 (m, 1H), 1.13 (d, J=6 Hz, 3H), 1.24 (m, 1H), 1.44 (m,1H), 1.76 (m, 3H), 1.98 (m, 1H), 2.14 (dd, J=12 Hz, J=6 Hz, 1H), 2.32(q, J=9 Hz, 1H), 2.43 (m, 1H), 2.94 (dd, J=12 Hz, J=6 Hz, 1H), 3.26 (m,1H), 7.00 (d, J=9 Hz, 2H), 7.36 (d, J=9 Hz, 2H). MS (DCl—NH₃) m/z 294(M+H)⁺.

Example 4B4′-((1R,2R)-2-{[(2S)-2-Methylpyrrolidin-1-yl]methyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrile

The title compound was prepared using the procedure described in Example3D substituting1-[2-(4-bromo-phenyl)-(1R,2R)-cyclopropylmethyl]-(2S)-2-methyl-pyrrolidine(the product from Example 4A) for1-[2-(4-bromo-phenyl)-(1R,2R)-cyclopropylmethyl]-(2R)-2-methyl-pyrrolidine(the product from Example 3C). ¹H NMR (300 MHz, CD₃OD)

1.22 (m, 2H), 1.42 (d, J=6 Hz, 3H), 1.53 (m, 1H), 1.76 (m, 1H), 2.08 (m,3H), 2.31 (m, 1H), 3.09 (dd, J=12 Hz, J=6 Hz, 1H), 3.23 (m, 1H), 3.39(dd, J=12 Hz, J=6 Hz, 1H), 3.50 (m, 1H), 3.67 (m, 1H), 7.27 (d, J=9 Hz,2H), 7.61 (d, J=6 Hz, 2H), 7.78 (s, 4H). MS (DCl—NH₃) m/z 317 (M+H)⁺.

Example 54′-{(1S,2S)-2-[(2-Methylpyrrolidin-1-yl)methyl]cyclopropyl}-1,1′-biphenyl-4-carbonitrileExample 5A1-[2-(4-Bromo-phenyl)-(1S,2S)-cyclopronylmethyl]-2-methyl-pyrrolidine

The title compound was prepared using the procedure described in Example1D substituting racemic 2-methylpyrrolidine for (S)-2-methylpyrrolidine.¹H NMR (300 MHz, CDCl₃):

0.87-0.92 (m, 1H), 0.97-1.02 (m, 1H), 1.16 (d, J=6 Hz, 2H), 1.22 (m,1H), 1.39-1.49 (m, 1H), 1.73-1.81 (m, 3H), 2.0 (m, 2H), 2.36 (q, J=6 Hz,1H), 2.45 (m, 1H), 3.13 (dd, J=12 Hz, J=6 Hz, 1H), 3.25 (m, 1H), 7.00(d, J=6 Hz, 2H), 7.37 (d, J=6 Hz, 2H). MS (DCl—NH₃) m/z 294 (M+H)⁺.

Example 5B4′-{(1S,2S)-2-[(2-Methylpyrrolidin-1-yl)methyl]cyclopropyl}-1,1′-biphenyl-4-carbonitrile

The title compound was prepared using the procedure described in Example1E substituting1-[2-(4-bromo-phenyl)-(1S,2S)-cyclopropylmethyl]-2-methyl-pyrrolidine(the product from Example 5A) for1-[(1S,2S)-2-(4-bromo-phenyl)-cyclopropylmethyl]-2(S)-methyl-pyrrolidine(the product from Example 1D). ¹H NMR (300 MHz, CD₃OD)

0.98 (m, 1H), 1.1 (m, 1H), 1.20 (d, J=6 Hz, 2H), 1.34 (m, 1H), 1.49 (m,1H), 1.84 (m, 3H), 2.06 (m, 2H), 2.51 (m, 1H), 2.61 (m, 1H), 3.06 (dd,J=12 Hz, J=6 Hz, 0.5H), 3.22 (dd, J=12 Hz, J=6 Hz, 0.5H), 3.34 (m, 1H),7.22 (dd, J=12 Hz, J=6 Hz, 2H), 7.59 (d, J=9 Hz, 2H), 7.77 (s, 4H)<MS(DCl—NH₃) m/z 317 (M+H)⁺.

Example 65-[4-((1S,2S)-2-{[(2S)-2-Methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidine

The title compound was prepared using the procedure described in Example1E substituting 5-pyrimidineboronic acid for 4-cyanophenylboronic acid.¹H NMR (300 MHz, CD₃OD) δ 0.96 (m, 1H), 1.09 (m, 1H), 1.16 (d, J=6 Hz,3H), 1.31 (m, 1H), 1.44 (m, 1H), 1.76 (m, 2H), 1.86 (m, 1H), 1.99 (m,2H), 2.35 (m, 1H), 2.41 (m, 1H), 3.29 (dd, J=12 Hz, J=6 Hz, 1H), 3.58(m, 1H), 7.26 (dd, J=12 Hz, J=6 Hz, 2H), 7.60 (d, J=9 Hz, 2H), 7.77 (s,4H) MS (DCl—NH₃) m/z 317 (M+H)⁺.

Example 72-Methoxy-5-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidine

The title compound was prepared using the procedure described in Example1E substituting 2-methoxy-5-pyrimidineboronic acid for4-cyanophenylboronic acid. ¹H NMR (300 MHz, CD₃OD) δ 0.94 (m, 1H), 1.05(m, 1H), 1.15 (d, J=6 Hz, 3H), 1.26 (m, 1H), 1.43 (m, 1H), 1.77 (m, 3H),1.94 (m, 2H), 2.32 (m, 2H), 3.21 (m, 2H), 4.04 (s, 1H), 7.21 (d, J=9 Hz,2H), 7.52 (d, J=9 Hz, 2H), 8.78 (s, 2H). MS (DCl—NH₃) m/z 324 (M+H)⁺.

Example 82,6-Dimethyl-3-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridine

The title compound was prepared using the procedure described in Example2B substituting2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine(prepared according to the procedure described in J. Org. Chem.67:7541-7543 (2002)) for 4-cyanophenylboronic acid, ¹H NMR (300 MHz,CD₃OD) δ 0.95 (m, 1H), 1.06 (m, 1H), 1.16 (d, J=6 Hz, 3H), 1.33 (m, 1H),1.47 (m, 1H), 1.80 (m, 3H), 2.00 (m, 1H), 2.20 (dd, J=12 Hz, J=6 Hz,1H), 2.37 (m, 2H), 2.41 (s, 3H), 2.48 (m, 1H), 2.52 (s, 3H), 3.0 (dd,J=12 Hz, J=6 Hz, 1H), 7.19 (m, 5H), 7.51 (d, J=9 Hz, 1H). MS (DCl—NH₃)m/z 321 (M+H)⁺.

Example 92-Methoxy-5-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridine

The title compound was prepared using the procedure described in Example2B substituting 2-methoxy-5-pyridineboronic acid for4-cyanophenylboronic acid. ¹H NMR (300 MHz, CD₃OD) δ 1.21 (m, 2H), 1.45(d, J=6 Hz, 3H), 1.50 (m, 1H), 1.76 (m, 1H), 2.00 (m, 3H), 2.34 (m, 1H),3.14 (dd, J=12 Hz, J=6 Hz, 1H), 3.27 (m, 1H), 3.44 (dd, J=12 Hz, J=6 Hz,1H), 3.54 (m, 1H), 3.73 (m, 1H), 3.95 (s, 3H), 6.88 (d, J=9 Hz, 1H),7.21 (d, J=9 Hz, 2H), 7.51 (d, J=9 Hz, 2H), 7.93 (dd, J=12 Hz, J=6 Hz,1H), 8.33 (d, J=3 Hz, 1H). MS (DCl—NH₃) m/z 323 (M+H)⁺.

Example 105-[4-((1S,2S)-2-{[(2R)-2-Methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidine

The title compound was prepared using the procedure described in Example2B substituting 5-pyrimidineboronic acid for 4-cyanophenylboronic acid¹H NMR (300 MHz, CD₃OD) δ 1.26 (m, 2H), 1.45 (d, J=6 Hz, 3H), 1.56 (m,1H), 1.76 (m, 1H), 2.09 (m, 3H), 2.35 (m, 1H), 3.12 (dd, J=12 Hz, J=6Hz, 1H), 3.26 (m, 1H), 3.46 (dd, J=12 Hz, J=6 Hz, 1H), 3.55 (m, 1H),3.73 (m, 1H), 7.32 (d, J=9 Hz, 2H), 7.66 (d, J=9 Hz, 2H), 9.04 (s, 2H),9.12 (s, 1H) MS (DCl—NH₃) m/z 317 (M+H)⁺.

Example 115-[4-((1R,2R)-2-{[(2S)-2-Methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidine

The title compound was prepared using the procedure described in Example4B substituting 5-pyrimidineboronic acid for 4-cyanophenylboronic acid¹H NMR (300 MHz, CD₃OD) δ 1.09 (m, 1H), 1.17 (m, 1H), 1.29 (d, J=6 Hz,3H), 1.45 (m, 1H), 1.61 (m, 1H), 1.95 (m, 3H), 2.16 (m, 1H), 2.66 (dd,J=12 Hz, J=6 Hz, 1H), 2.79 (q, J=9 Hz, 1H), 2.99 (m, 1H), 3.20 (dd, J=12Hz, J=6 Hz, 1H), 3.49 (m, 1H), 7.29 (d, J=9 Hz, 2H), 7.63 (d, J=9 Hz,2H), 9.03 (s, 2H), 9.10 (s, 1H). MS (DCl—NH₃) m/z 317 (M+H)⁺.

Example 125-[4-((1R,2R)-2-{[(2R)-2-Methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidine

The title compound was prepared using the procedure described in Example3D substituting 5-pyrimidineboronic acid for 4-cyanophenylboronic acid.¹H NMR (300 MHz, CD₃OD) δ 1.00 (m, 1H), 1.11 (m, 1H), 1.21 (d, J=6 Hz,3H), 1.34 (m, 1H), 1.51 (m, 1H), 1.82 (m, 2H), 1.90 (m, 1H), 2.08 (m,1H), 2.18 (m, 1H), 2.53 (q, J=9 Hz, 1H), 2.62 (m, 1H), 3.23 (dd, J=12Hz, J=6 Hz, 1H), 3.34 (m, 1H), 7.27 (d, J=9 Hz, 2H), 7.62 (d, J=9 Hz,2H), 9.03 (s, 2H), 9.10 (s, 1H). MS (DCl—NH₃) m/z 317 (M+H)⁺.

Example 132,4-Dimethoxy-5-[4-((1R,2R)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidine

The title compound was prepared using the procedure described in Example4B substituting 2,6-dimethoxy-5-pyrimidineboronic acid for4-cyanophenylboronic acid. ¹H NMR (300 MHz, CD₃OD) δ 1.03 (m, 1H), 1.11(m, 1H), 1.27 (d, J=6 Hz, 3H), 1.39 (m, 1H), 1.59 (m, 1H), 1.93 (m, 3H),2.15 (m, 1H), 2.58 (dd, J=12 Hz, J=6 Hz, 1H), 2.73 (q, J=9 Hz, 1H), 2.91(m, 1H), 3.15 (dd, J=12 Hz, J=6 Hz, 1H), 3.45 (m, 1H), 4.03 (s, 6H),7.16 (d, J=9 Hz, 2H), 7.40 (d, J=9 Hz, 2H), 8.22 (s, 1H). MS (DCl—NH₃)m/z 354 (M+H)⁺.

Example 142,4-Dimethoxy-5-[4-((1R,2R)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopronyl)phenyl]pyrimidine

The title compound was prepared using the procedure described in Example3D substituting 2,6-dimethoxy-5-pyrimidineboronic acid for4-cyanophenylboronic acid, ¹H NMR (300 MHz, CD₃OD) δ 1.04 (m, 1H), 1.15(m, 1H), 1.31 (d, J=6 Hz, 3H), 1.38 (m, 1H), 1.62 (m, 1H), 1.97 (m, 3H),2.18 (m, 1H), 2.57 (dd, J=12 Hz, J=6 Hz, 1H), 2.87 (q, J=9 Hz, 1H), 3.02(m, 1H), 3.34 (dd, J=12 Hz, J=6 Hz, 1H), 3.50 (m, 1H), 4.03 (s, 6H),7.16 (d, J=9 Hz, 2H), 7.41 (d, J=9 Hz, 2H), 8.22 (s, 1H). MS (DCl—NH₃)m/z 354 (M+H)⁺.

Example 152,4-Dimethoxy-5-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidine

The title compound was prepared using the procedure described in Example2B substituting 2,6-dimethoxy-5-pyrimidineboronic acid for4-cyanophenylboronic acid, ¹H NMR (300 MHz, CD₃OD) δ 1.04 (m, 1H), 1.12(m, 1H), 1.28 (d, J=6 Hz, 3H), 1.39 (m, 1H), 1.60 (m, 1H), 1.94 (m, 3H),2.15 (m, 1H), 2.65 (dd, J=12 Hz, J=6 Hz, 1H), 2.78 (q, J=9 Hz, 1H), 2.98(m, 1H), 3.17 (dd, J=12 Hz, J=6 Hz, 1H), 3.47 (m, 1H), 4.03 (s, OH),7.17 (d, J=9 Hz, 2H), 7.41 (d, J=9 Hz, 2H), 8.22 (s, 1H). MS (DCl—NH₃)m/z 354 (M+H)⁺.

Example 162,4-Dimethoxy-5-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidine

The title compound was prepared using the procedure described in Example1E substituting 2,6-dimethoxy-5-pyrimidineboronic acid for4-cyanophenylboronic acid ¹H NMR (300 MHz, CD₃OD) δ 1.04 (m, 1H), 1.12(m, 1H), 1.28 (d, J=6 Hz, 3H), 1.39 (m, 1H), 1.60 (m, 1H), 1.94 (m, 3H),2.15 (m, 1H), 2.65 (dd, J=12 Hz, J=6 Hz, 1H), 2.78 (q, J=9 Hz, 1H), 2.98(m, 1H), 3.17 (dd, J=12 Hz, J=6 Hz, 1H), 3.47 (m, 1H), 4.03 (s, 6H),7.17 (d, J=9 Hz, 2H), 7.41 (d, J=9 Hz, 2H), 8.22 (s, 1H). MS (DCl—NH₃)m/z 354 (M+H)⁺.

Example 172-[4-((1R,2R)-2-{[(2S)-2-Methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-one

A solution of the product from Example 4A (47 mg, 0.16 mmol;1-[2-(4-bromo-phenyl)-(1R,2R)-cyclopropylmethyl]-(2S)-2-methyl-pyrrolidine),3(2H)-pyridazinone (CAS #504-30-3, 20 mg, 0.2 mmol), copper iodide (1.5mg, 0.008 mmol), N,N′-trans-dimethyl-cyclohexane-1,2-diamine (2.3 mg,0.016 mmol) and potassium phosphate (75 mg, 0.35 mmol) in a mixture oftoluene and isopropanol (4 ml, 1.1) was heated to 110° C. in a screwcapped vial for 16 hours. The mixture was cooled to ambient temperature,treated with H₂O and extracted with ethyl acetate (2×25 mL) The organiclayer was separated, washed with brine and dried with magnesium sulfate.After filtration, the organic layer was concentrated under reducedpressure and the resulting oil was purified on silica gel with 1% to 3%methanol (containing 10% concentrated NH₄OH) in dichloromethane toprovide the title compound. ¹H NMR (300 MHz, CD₃OD) δ 1.07 (m, 1H), 1.14(m, 1H), 1.26 (d, J=6 Hz, 3H), 1.40 (m, 1H), 1.58 (m, 1H), 1.90 (m, 3H),2.13 (m, 1H), 2.58 (m, 1H), 2.70 (q, J=9 Hz, 1H), 2.89 (m, 1H), 3.14(dd, J=12 Hz, J=6 Hz, 1H), 3.44 (m, 1H), 7.07 (d, J=9 Hz, 1H), 7.24 (d,J=9 Hz, 2H), 7.44 (d, J=9 Hz, 2H), 7.47 (m, 1H), 8.03 (m, 1H), MS(DCl—NH₃) m/z 310 (M+H)⁺.

Example 182-[4-((1S,2S)-2-{[(2S)-2-Methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-one

The title compound was prepared using the procedure described in Example17 substituting the product from Example 1D1-[(1S,2S)-2-(4-bromo-phenyl)-cyclopropylmethyl]-2(S)-methyl-pyrrolidineas starting material in place of the1-[2-(4-Bromo-phenyl)-(1R,2R)-cyclopropylmethyl]-(2S)-2-methyl-pyrrolidine.¹H NMR (300 M Hz, CD₃OD) δ 0.97 (m, 1H), 1.13 (m, 1H), 1.23 (d, J=6 Hz,3H), 1.34 (m, 1H), 1.51 (m, 1H), 1.85 (m, 3H), 1.93 (m, 1H), 2.01 (m,1H), 2.68 (q, J=9 Hz, 1H), 2.85 (m, 1H), 3.08 (m, 1H), 3.23 (m, 1H),7.07 (d, J=9 Hz, 1H), 7.22 (d, J=9 Hz, 2H), 7.44 (d, J=9 Hz, 2H), 7.47(m, 1H), 8.03 (m, 1H). MS (DCl—NH₃) m/z 310 (M+H)⁺.

Example 19N-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]-1H-1,2,4-triazole-3-carboxamide

The title compound was prepared using the procedure described in Example34G substituting 1H-1,2,4-triazole-3-carboxamide forpyridazin-3(2H)-one. ¹H NMR (300 MHz, CD₃OD) δ 1.11-1.18 (m, 1H),1.22-1.28 (m, 1H), 1.38 (d, J=6 Hz, 3H), 1.47-1.53 (m, 1H), 1.67-1.74(m, 1H), 2.01-2.15 (m, 3H), 2.24-2.35 (m, 1H), 2.91-2.99 (m, 1H),3.13-3.23 (m, 1H), 3.33-3.43 (m, 2H), 3.60-3.68 (m, 1H), 7.34 (d, J=9Hz, 2H), 7.79 (d, J=9 Hz, 2H), 9.05 (s, 1H) MS (DCl—NH₃) m/z 326 (M+H)⁺.

Example 202-Methyl-5-[4-(1S,2S-2-{[(2S)-2-methylprrolidin-1-yl]methyl}cyclopropyl)phenyl]-1,3-benzothiazoleExample 20A2-Methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzothiazole

A solution of 5-bromo-2-methyl-benzothiazole (2 g, 8.8 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.7 g, 10.6mmol; CAS 73183-34-3), potassium acetate (3.1 g, 31.7 mmol) andPd(dppf)₂Cl₂ dichloromethane complex (1:1) (360 mg, 0.51 mmol) inanhydrous tetrahydrofuran (70 mL) under a nitrogen atmosphere was heatedto reflux overnight. After cooling to ambient temperature, the mixturewas filtered through diatomaceous earth and washed with ethyl acetate.The filtrate was washed with water and brine, dried (MgSO₄), filteredand concentrated under reduced pressure. The residue was chromatographedon silica gel eluting with 10% ethyl acetate in hexanes to provide thetitle compound. ¹H NMR (300 MHz, CD₃Cl₃) δ 1.37 (s, 12H), 2.84 (s, 3H),7.75 (d, J=9 Hz, 1H), 7.82 (d, J=9 Hz, 1H), 8.38 (s, 1H), (DCl/NH₃) m/z276 (M+H)⁺.

Example 20B2-Methyl-5-[4-(1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]-1,3-benzothiazole

The title compound was prepared using the procedure described in Example1E substituting the product from Example 20A for 4-cyanophenylboronicacid, ¹H NMR (300 MHz, CD₃OD) δ 1.01 (m, 1H), 1.14 (m, 1H), 1.26 (d, J=6Hz, 3H), 1.35 (m, 1H), 1.55 (m, 1H), 1.91 (m, 3H), 2.12 (m, 1H), 2.34(m, 1H), 2.67 (m, 1H), 2.75 (m, 1H), 2.85 (s, 3H), 3.26 (m, 2H), 3.41(m, 1H), 7.21 (d, J=9 Hz, 2H), 7.60 (d, J=9 Hz, 2H), 7.65 (dd, J=9 Hz,J=3 Hz, 1H), 7.96 (d, J=6 Hz, 1H), 8.06 (d, J=3 Hz, 1H). MS (DCl—NH₃)m/z 362 (M+H)⁺.

Example 211,3,5-Trimethyl-4-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]-1H-pyrazole

The title compound was prepared using the procedure described in Example1E substituting1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(CAS #844891-04-9) for 4-cyanophenylboronic acid. ¹H NMR (300 MHz,CD₃OD) δ 0.99 (m, 1H), 1.07 (m, 1H), 1.22 (d, J=6 Hz, 3H), 1.29 (m, 1H),1.51 (m, 1H), 1.86 (m, 3H), 2.08 (m, 1H), 2.15 (s, 3H), 2.18 (m, 1H),2.21 (s, 3H), 2.56 (m, 1H), 2.65 (m, 1H), 3.24 (m, 1H), 3.38 (m, 1H),7.14 (s, 4H). MS (DCl—NH₃) m/z 324 (M+H)⁺.

Example 222,6-Dimethyl-3-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridine

The title compound was prepared using the procedure described in Example1E substituting 2,6-dimethylpyridine-3-boronic acid for4-cyanophenylboronic acid. ¹H NMR (300 MHz, CD₃OD) δ 0.97 (m, 1H), 1.09(m, 1H), 1.22 (d, J=6 Hz, 3H), 1.32 (m, 1H), 1.51 (m, 1H), 1.86 (m, 3H),2.07 (m, 1H), 2.18 (m, 1H), 2.41 (s, 3H), 2.52 (s, 3H), 2.55 (m, 1H),2.62 (m, 1H), 3.25 (m, 1H), 3.37 (m, 1H), 7.19 (m, 5H), 7.49 (d, J=9 Hz,1H), MS (DCl—NH₃) m/z 321 (M+H)⁺.

Example 235-[4-((1S,2S)-2-{[(2S)-2-Methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidine

The title compound was prepared using the procedure described in Example1E substituting pyrimidine-3-boronic acid for 4-cyanophenylboronic acid¹H NMR (300 MHz, CD₃OD) δ 0.96 (m, 1H), 1.1 (m, 1H), 1.16 (d, J=6 Hz,3H), 1.31 (m, 1H), 1.45 (m, 1H), 1.77 (m, 2H), 1.86 (m, 1H), 2.0 (m,2H), 2.4 (m, 2H), 3.18 (m, 1H), 3.27 (m, 1H), 7.26 (d, J=9 Hz, 2H), 7.62(d, J=9 Hz, 2H), 9.03 (s, 2H), 9.09 (s, 1H). MS (DCl—NH₃) m/z 294(M+H)⁺.

Example 24N-isobutyl-N-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]amineExample 24A4-{2-[(2S)-2-Methyl-pyrrolidin-1-ylmethyl]-(1S,2S)-cyclopropyl}-phenylamine

A solution of the product from Example 1D (640 mg, 2.18 mmol,1-[(1S,2S)-2-(4-bromo-phenyl)-cyclopropylmethyl]-2(S)-methyl-pyrrolidine),lithium bis(trimethylsilyl)amide (560 mg), Pd₂(dba)₃ (100 mg) andP(t-Bu)₃ (10% in hexane, 530 mg) in toluene (3 mL) was heated in amicrowave reactor at 160° C. for 40 minutes. The mixture was dilutedwith dichloromethane and H₂O and partitioned. The aqueous layer wasextracted with DCM and the organic layers were combined, dried andconcentrated to afford a brownish residue which was purified on silicagel eluting with 3% methanol (containing 10% concentrated NH₄OH) indichloromethane to provide the title compound. ¹H NMR (300 MHz, CD₃OD) δ0.73 (m, 1H), 0.85 (m, 1H), 1.07 (m, 1H), 1.13 (d, J=6 Hz, 3H), 1.41 (m,1H), 1.63 (m, 1H), 1.76 (m, 3H), 2.0 (m, 1H), 2.28 (m, 2H), 3.12 (m,1H), 3.27 (m, 1H), 6.65 (d, J=9 Hz, 2H), 6.83 (d, J=9 Hz, 2H). MS(DCl—NH₃) m/z 231 (M+H)⁺.

Example 24BN-Isobutyl-N-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]amine

A solution of the product from Example 24A (35 mg, 0.15 mmol,4-{2-[(2S)-2-methyl-pyrrolidin-1-ylmethyl]-(1S,2S)-cyclopropyl}-phenylamine)and 2-methyl-propionaldehyde (20 mL, 0.23 mmol) in ethanol (8 mL) wastreated with borane-pyridine (30 mL) at room temperature and stirred for16 hours. The mixture was concentrated and the residue was purified onsilica gel eluting with 3% methanol (containing 10% concentrated NH₄OH)in dichloromethane to provide the title compound. ¹H NMR (300 MHz,CD₃OD) δ 0.82 (m, 1H), 0.94 (m, 1H), 0.95 (d, J=9 Hz, 6H), 1.17 (m, 1H),1.26 (d, J=6 Hz, 3H), 1.57 (m, 1H), 1.76 (m, 2H), 1.90 (m, 3H), 2.13 (m,1H), 2.37 (m, 1H), 2.75 (m, 1H), 2.84 (m, 3H), 3.23 (m, 1H), 3.45 (m,1H), 6.56 (d, J=9 Hz, 2H), 6.86 (d, J=9 Hz, 2H). MS (DCl—NH₃) m/z 287(M+H)⁺.

Example 25N-[4-((1S,2S)-2-{[(2S)-2-Methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidin-5-amine

A solution of the product from Example 24A (300 mg, 1.3 mmol,4-{2-[(2S)-2-methyl-pyrrolidin-1-ylmethyl]-(1S,2S)-cyclopropyl}-phenylamine),5-bromopyrimidine (311 mg, 1.95 mmol),tris(dibenzylidineacetone)dipalladium(0)•chloroform (40 mg), Cs₂CO₃ (1g), and 1,1′-bis(diphenylphosphino)ferrocene (65 mg) in anhydrousdioxane (8 mL) was heated to 110° C. for 48 hours. The mixture wascooled to room temperature, diluted with EtOAc and washed with water andbrine. The organic layer was dried (MgSO₄), filtered, concentrated underreduced pressure, and purified on silica gel eluting with 3% methanol(containing 10% concentrated NH₄OH) in dichloromethane to provide thetitle compound. ¹H NMR (300 MHz, CD₃OD) δ 0.84 (m, 1H), 0.96 (m, 1H),1.14 (d, J=6 Hz, 3H), 1.20 (m, 1H), 1.43 (m, 1H), 1.75 (m, 3H), 1.88 (m,1H), 2.01 (m, 1H), 2.28 (m, 1H), 2.35 (m, 1H), 3.14 (m, 1H), 3.26 (m,1H), 7.08 (s, 4H), 8.44 (s, 2H), 8.51 (s, 1H). MS (DCl—NH₃) m/z 309(M+H)⁺.

Example 264′-((1R,2S)-2-{2-[(2R)-2-Methylpyrrolidin-1-yl]ethyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrileExample 26A 3-(4-Bromophenyl)prop-2-ene 1-ol

To a solution of ethyl trans-4-bromocinnamate [CAS 24393-53-1] (8 mL,42.6 mmol) in anhydrous dichloromethane (150 mL) under N₂ was addeddropwise diisobutylaluminum hydride in dichloromethane (128 mL, 1M, 128mmol) at −78° C. Following the addition, the mixture was allowed to warmfrom −78° C. to −30° C. over two hours. The mixture was then cooled backto −78° C. and aqueous 1 N HCl was added. The organic layer wasseparated, dried with MgSO₄, filtered and concentrated under reducedpressure to provide the title compound, ¹H NMR (300 MHz, CDCl₃): δ 1.44(t, J=6 Hz, 1H), 4.32 (t, J=4.5 Hz, 2H), 6.37 (dt, J=16.5 Hz, J=6 Hz,1H), 6.57 (dt, J=15 Hz, J=3 Hz, 1H), 7.25 (d, J=9 Hz, 2H), 7.45 (d, J=9Hz, 2H). MS (DCl—NH₃) m/z 214 (M+H)⁺.

Example 26B 2-Butyl-[1,3,2]dioxaborolane-(S,S)-4,5-dicarboxylic acidbis-dimethylamide

2-(But-1-yl)-tetrahydro-4H-1,3,6,2-dioxazaborocine [CAS 92527-13-4] wasprepared from n-butylboronic acid and 2-(2-hydroxy-ethylamino)-ethanol[CAS 111-42-2] as reported in Organic Synthesis, 1998, 76, 86-96. Thisdioxazaborocine (3 g, 17.5 mmol) and(2S,3S)-2,3-dihydroxy-N,N,N′,N′-tetramethyl-butanediamide [CAS63126-52-3] (4.65 g) were dissolved in anhydrous dichloromethane (95 mL)under N₂. Brine (30 mL) was added. The resulting mixture was stirred atroom temperature for 1 hour. The two layers were separated, and theaqueous layer was extracted with dichloromethane (30 mL). The combinedorganic layers were washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo to provide the title compound as an oil ¹H NMR(300 MHz, CDCl₃): δ 0.82-0.9 (m, 5H), 1.25-1.45 (m, 4H), 2.98 (s, 6H),3.2 (s, 6H), 5.52 (s, 2H). MS (DCl—NH₃) m/z 271 (M+H)⁺.

Example 26C (1R,2R)-[2-(4-Bromophenyl)cyclopropyl]methanol

To a −10° C. solution of dimethoxyethane (1.2 mL, 2 equivalents) inanhydrous dichloromethane (30 mL) under N₂ was added dropwise,diethylzinc (12 mL, 1M in dichloromethane) followed by dropwise additionof diiodomethane (1.8 mL) over 15 minutes, maintaining the temperaturebelow −5° C. The mixture was stirred another 10 minutes at −10° C. afterthe addition, then a solution of the dioxaborolane from Example 26B (1.8g in 5 mL dichloromethane) was added over 6 minutes at −5° C. A solutionof the alkene from Example 26A (1 g in 5 mL dichloromethane) was thenadded dropwise. The cooling bath was removed and the mixture was stirredovernight. The mixture was quenched with the addition of saturatedaqueous NH₄Cl, and 10% aqueous HCl. This mixture was extracted withether twice. The combined organic extracts were treated with aqueous 2NNaOH (40 mL) and 30% aqueous H₂O₂ (5 mL) and then stirred for 5 minutes.The separated organic layer was then washed sequentially with 10%aqueous HCl, aqueous Na₂S₂O₃, aqueous NaHCO₃, and brine. The organiclayer was dried (MgSO₄) and filtered. The filtrate was concentrated invacuo. The residue was purified on silica gel eluting with 4:1hexanes/ethyl acetate to provide the title compound.

¹H NMR (300 MHz, CDCl₃): δ 0.92-1.0 (m, 2H), 1.45-1.48 (m, 2H),1.76-1.85 (m, 1H), 3.61 (d, J=7.5 Hz, 2H), 6.95 (d, J=9 Hz, 2H), 7.37(d, J=9 Hz, 2H). MS (DCl—NH₃) m/z 228 (M+H)⁺.

Example 26D (1R,2R)-2-(4-Bromophenyl)cyclopropanecarbaldehyde

DMSO (0.8 mL, 3 equivalents) was added dropwise to a solution of oxalylchloride (0.48 mL) in anhydrous dichloromethane (50 mL) under N₂ at −78°C. A solution of the alcohol from Example 26C (823 mg) indichloromethane (20 mL) was then added dropwise at −78° C. Stirring atthis temperature was continued for 30 minutes, then triethylamine (2 mL,4 equivalents) was added, and the dry ice bath was removed. Afterstirring for 1 hour, the mixture was treated with saturated aqueousNH₄Cl. The mixture was extracted with ether. The combined organicextracts was dried (MgSO₄) and filtered. The filtrate was concentratedunder reduced pressure. The residue was purified by eluting through apad of silica gel with hexane to provide the title compound. ¹H NMR (300MHz, CDCl₃): δ 1.48 (m, 1H), 1.65 (dt, J=9 Hz, J=6 Hz, 1H), 2.15 (m,1H), 2.57 (m, 1H), 6.98 (d, J=9 Hz, 2H), 7.45 (d, J=9 Hz, 2H), 9.46 (d,J=4.5 Hz, 1H). MS (DCl—NH₃) m/z 226 (M+H)⁺.

Example 26E 1-Bromo-4-[(1R,2S)-2-vinvicyclopropyl]benzene

A solution of the aldehyde from Example 26D (500 mg, 2.22 mmol) andmethyltriphenylphosphonium iodide [CAS 2065-66-9] (1.17 g) in anhydrousdichloromethane (50 mL) was stirred at 0° C. under N₂. Potassiumt-butoxide (340 mg) was added to this chilled mixture. The ice bath wasremoved, and the mixture was stirred at room temperature for one hour.The mixture was quenched with saturated aqueous NH₄Cl. The mixture wasextracted with dichloromethane and the combined organic extracts weredried (MgSO₄) and filtered. The filtrate was concentrated under reducedpressure and the residue was purified on silica gel with hexanes toprovide the title compound. ¹H NMR (300 MHz, CDCl₃); δ 1.1-1.2 (m, 2H),1.6-1.7 (m, 1H), 1.84-1.92 (m, 1H), 5.05 (ddd, J=34 Hz, J=9 Hz, J=1 Hz,1H), 5.52 (ddd, J=18 Hz, J=10 Hz, J=9 Hz, 1H), 6.95 (d, J=9 Hz, 2H),7.45 (d, J=9 Hz, 2H), MS (DCl—NH₃) m/z 224 (M+H)⁺.

Example 26F 2-[(1S,2R)-2-(4-Bromophenyl)cycloprop-1-yl]ethanol

To a solution of the alkene from Example 26E (2.25 g, 10 mmol) inanhydrous THF (50 mL) under N₂ was added borane-THF (13 mL, 1M) at 0° C.The mixture was stirred at room temperature for two hours then chilledto 0° C. Aqueous hydrogen peroxide solution (35%, 3.5 mL) was added, theice bath was removed the mixture was allowed to warm to room temperatureand stirring was continued for 10 minutes. The mixture was quenched withsaturated aqueous NH₄Cl and extracted with ether. The combined organicextracts were dried (MgSO₄) and filtered. The filtrate was concentratedunder reduced pressure. The residue was purified on silica gel with 4:1hexanes/ethyl acetate to provide the title compound. ¹H NMR (300 MHz,CDCl₃) δ 0.8-0.92 (m, 2H), 1.02-1.1 (m, 1H), 1.46 (s, 1H), 1.6-1.7 (m,2H), 3.75 (t, J=6 Hz, 2H), 6.9 (d, J=9 Hz, 2H), 7.45 (d, J=9 Hz, 2H). MS(DCl—NH₃) m/z 241 (M+H)⁺.

Example 26G4′-[(1R,2S)-2-(2-Hydroxyethyl)cycloprop-1-yl]biphenyl-4-carbonitrile

A solution of Example 26F (1.2 g, 5 mmol), 4-cyanophenylboronic acid[CAS 126747-14-6] (1.46 g, 2 equivalents), Pd(PPh₃)₂Cl₂ (350 mg), andCs₂CO₃ (6.5 g) in isopropanol (80 mL) under N₂ was stirred at refluxovernight. The mixture was partitioned between ethyl acetate and H₂O.The organic layer was washed with saturated aqueous NaHCO₃ and then withbrine. The organic layer was then dried (MgSO₄) and filtered. Thefiltrate was concentrated in vacuo and the resulting residue waspurified by chromatography on silica gel eluted with 4.1 hexanes/ethylacetate to provide the title compound. ¹H NMR (300 MHz, CDCl₃): δ0.85-1.03 (m, 2H), 1.12-1.2 (m, 1H), 1.65-1.7 (m, 3H), 3.78 (t, J=6 Hz,2H), 7.15 (d, J=9 Hz, 2H), 7.48 (d, J=9 Hz, 2H), 7.68 (q, J=9 Hz, 4H).MS (DCl—NH₃) m/z 264 (M+H)⁺.

Example 26H Methanesulfonic acid,2-[1S,2R)-2-(4′-cyano-biphenyl-4-yl)-cyclopropyl]-ethyl ester

To a solution of Example 26G (560 mg, 2.13 mmol) and methanesulfonylchloride (0.22 mL, 1.2 equivalents) in dichloromethane (10 mL) under N₂was added triethylamine (0.42 mL, 1.4 equivalents) at 0° C. The mixturewas stirred at room temperature for 5 hours. The mixture was treatedwith H₂O, and the organic layer was washed with brine, then dried(MgSO₄) and filtered. The filtrate was concentrated in vacuo and theresulting residue was purified by chromatography on silica gel elutedwith 4:1 hexanes/ethyl acetate to provide the title compound. ¹H NMR(300 MHz, CDCl₃): δ 0.9-1.08 (m, 2H), 1.18-2.02 (m, 2H), 3.0 (s, 3H),4.35 (t, J=6 Hz, 2H), 7.15 (d, J=9 Hz, 2H), 7.48 (d, J=9 Hz, 2H), 7.68(q, J=9 Hz, 2H). MS (DCl—NH₃) m/z 342 (M+H)⁺.

Example 26I4′-((1S,2S)-2-{2-[(2R)-2-Methylpyrrolidin-1-yl]ethyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrile

To a solution of the mesylate from Example 26H (500 mg, 1.47 mmol) andpotassium carbonate (0.446 g, 3.24 mmol) in DMF (10 mL) was added(R)-2-methylpyrrolidine hydrobromide [CAS 117607-13-3] (300 mg, 1.81mmol). The mixture was stirred at 50° C. overnight. The mixture waspartitioned between ethyl acetate and H₂O. The organic layer was washedwith brine, dried (MgSO₄), and concentrated in vacuo. The resultingresidue was purified by chromatography on silica gel eluted with7.5/20/70 MeOH/EtOAc/CH₂Cl₂ to provide the title compound. ¹H NMR (300MHz, CDCl₃, free base): δ 0.85-0.9 (m, 1H), 1.03-1.0 (m, 1H), 1.14 (d,J=6 Hz, 3H), 1.4-2.4 (m, 11H), 2.9 (m, 1H), 3.15-3.23 (m, 1H), 7.15 (d,J=9 Hz, 2H), 7.47 (d, J=9 Hz, 2H), 7.66 (q, J=9 Hz, 4H). MS (DCl—NH₃)m/z 331.2 (M+H)⁺. Anal Calc. for C₂₃H₂₆N₂ C₄H₆O₆ 1.25H₂O (L-tartaricacid salt): C, 64.46; H, 6.91, N, 5.57. Found: C, 64.46; H, 6.91, N,5.57.

Example 27(2R)-1-{2-[(2S,2R)-2-(4-Bromophenyl)cyclopropyl]ethyl}-2-methylpyrrolidineExample 27A (1S,2R)-Methanesulfonic acid2-[2-(4-bromo-phenyl)-cyclopropyl]-ethyl ester

The alcohol from Example 26F,2-[(1S,2R)-2-(4-bromophenyl)cycloprop-1-yl]ethanol, was converted to(1S,2R)-methanesulfonic acid 2-[2-(4-bromo-phenyl)-cyclopropyl]-ethylester according to the methods outlined in Example 26H.

Example 27B(2R)-1-{2-[(1S,2R)-2-(4-Bromophenyl)cyclopropyl]ethyl}-2-methylpyrrolidine

The title compound was prepared according to the methods outlined inExample 26I substituting the product from Example 27A,(1R,2R)-methanesulfonic acid 2-[2-(4-bromo-phenyl)-cyclopropyl]-ethylester, for the product from Example 26H. ¹H NMR (300 MHz, CDCl₃, freebase): δ 0.75-0.9 (m, 2H), 0.97-1.04 (m, 1H), 1.15 (d, J=6 Hz, 3H),1.5-1.65 (m, 8H), 1.85-2.35 (m, 3H), 2.85-2.95 (m 1H), 3.12-3.20 (m,1H), 6.9 (d, J=9 Hz, 2H), 7.33 (d, J=9 Hz, 2H). MS (DCl—NH₃) m/z 310(M+H)⁺.

Example 284′-((1S,2R)-2-{2-[(2R)-2-Methylpyrrolidin-1-yl]ethyl}cycloprop-1-yl)-1,1′-biphenyl-4-carbonitrileExample 28A 2-Butyl-[1,3,2]dioxaborolane-(R,R)-4,5-dicarboxylic acidbis-dimethylamide

2-(But-1-yl)-tetrahydro-4H-1,3,6,2-dioxazaborocine [CAS 92527-13-4] (3g, 17.5 mmol), which was prepared from n-butylboronic acid and2-(2-hydroxy-ethylamino)-ethanol [CAS 111-42-2] as reported in OrganicSynthesis, 1998, 76, 86-96, and(2R,3R)-2,3-dihydroxy-N,N,N′,N′-tetramethyl-butanediamide [CAS26549-65-5] (9.85 g) were dissolved in anhydrous dichloromethane (160mL) under N₂, Brine (25 mL) was added. The resulting mixture was stirredat room temperature for about 16 hours. The two layers were separated,and the aqueous layer was extracted with dichloromethane. The combinedorganic layers were washed with 50 mL brine, dried over MgSO₄, filteredand concentrated in vacuo to provide the title compound as an oil.

Example 28B (1S,2S)-[2-(4-Bromophenyl)cyclopropyl]methanol

To a −10° C. solution of dimethoxyethane (5.2 mL) in anhydrousdichloromethane (200 mL) under N₂ was added dropwise, diethylzinc (62.6mL, 1M in dichloromethane) followed by dropwise addition ofdiiodomethane (10.1 mL), maintaining the temperature below −5° C. Themixture was stirred another 10 minutes at −10° C. after the addition,then a solution of the dioxaborolane(2-butyl-[1,3,2]dioxaborolane-(R,R)-4,5-dicarboxylic acidbis-dimethylamide) (8.8 g in 40 mL dichloromethane) was added at −5° C.A solution of the alkene from Example 26A (3-(4-bromophenyl)prop-2-1-ol,5.3 g in 50 mL dichloromethane) was then added dropwise. The coolingbath was removed and the mixture was stirred overnight. The mixture wasquenched with the addition of saturated aqueous NH₄Cl, and 10% aqueousHCl. This mixture was extracted with ether twice. The combined organicextracts were treated with aqueous 2N NaOH (250 mL) and 30% aqueous H₂O₂(35 mL) and then stirred for 5 minutes. The organic layer was thenwashed sequentially with 10% aqueous HCl, aqueous Na₂S₂O₃, aqueousNaHCO₃₇ and brine. The organic layer was dried (MgSO₄) and filtered. Thefiltrate was concentrated in vacuo. The residue was purified on silicagel eluting with hexanes/ethyl acetate to provide the title compound.

Example 28C (1S,2S)-2-(4-Bromophenyl)cyclopropanecarbaldehyde

DMSO (3 equivalents) was added dropwise to a solution of oxalyl chloridein anhydrous dichloromethane under N₂ at −78° C. A solution of thealcohol from Example 28B((1S,2S)-[2-(4-bromophenyl)cyclopropyl]methanol) in dichloromethane wasthen added dropwise at −78° C. Stirring at this temperature wascontinued for 30 minutes, then triethylamine (4 equivalents) was addedand the dry ice bath was removed. After stirring for 1 hour, the mixturewas treated with saturated aqueous NH₄Cl. The mixture was extracted withether. The combined organic extracts was dried (MgSO₄) and filtered. Thefiltrate was concentrated under reduced pressure. The residue waspurified by eluting through a pad of silica gel with hexane to providethe title compound.

Example 28D 1-Bromo-4-[(1S,2R)-2-vinylcyclopropyl]benzene

A solution of the aldehyde from Example 28C[(1S,2S)-2-(4-bromophenyl)cyclopropanecarbaldehyde] andmethyltriphenylphosphonium iodide [CAS 2065-66-9] in anhydrousdichloromethane was stirred at 0° C. under N₂. Potassium t-butoxide wasadded to this chilled mixture. The ice bath was removed and the mixturewas stirred at room temperature for one hour. The mixture was quenchedwith saturated aqueous NH₄Cl. The mixture was extracted withdichloromethane and the combined organic extracts were dried (MgSO₄) andfiltered. The filtrate was concentrated under reduced pressure and theresidue was purified on silica gel with hexanes to provide the titlecompound.

Example 28E 2-[(1R,2S)-2-(4-Bromophenyl)cycloprop-1-yl]ethanol

To a solution of the alkene from Example 28D(1-bromo-4-[(1S,2R)-2-vinylcyclopropyl]benzene) in anhydrous THF (50 mL)under N₂ was added borane-THF at 0° C. The mixture was stirred at roomtemperature for two hours and then chilled to 0° C. Aqueous hydrogenperoxide (30%) solution was added, the ice bath was removed, and themixture was allowed to warm to room temperature with continued stirringfor 10 minutes. The mixture was quenched with saturated aqueous NH₄Cland extracted with ether. The combined organic extracts were dried(MgSO₄) and filtered. The filtrate was concentrated under reducedpressure. The residue was purified on silica gel with 4:1 hexanes/ethylacetate to provide the title compound.

Example 28F4′-[(1S,2R)-2-(2-Hydroxyethyl)cycloprop-1-yl]biphenyl-4-carbonitrile

A solution of the product of Example 28E(2-[(1R,2S)-2-(4-bromophenyl)cycloprop-1-yl]ethanol),4-cyanophenylboronic acid [CAS 126747-14-6] (2 equivalents),Pd(PPh₃)₂Cl₂, and Cs₂CO₃ in isopropanol under N₂ was stirred at refluxovernight. The mixture was partitioned between ethyl acetate and H₂O.The organic layer was washed with saturated aqueous NaHCO₃ and then withbrine. The organic layer was then dried (MgSO₄) and filtered. Thefiltrate was concentrated in vacuo and the resulting residue waspurified by chromatography on silica gel eluted with 4:1 hexanes/ethylacetate to provide the title compound.

Example 28G Methanesulfonic acid,2-[(1R,2S)-2-(4′-cyano-biphenyl-4-yl)-cyclopropyl]-ethyl ester

To a solution of the product of Example 28F(4′-[(1S,2R)-2-(2-hydroxyethyl)cycloprop-1 yl]biphenyl-4-carbonitrile)and methanesulfonyl chloride (1.2 equivalents) in dichloromethane underN₂ was added triethylamine (1.4 equivalents) at 0° C. The mixture wasstirred at room temperature overnight, and then the mixture was treatedwith H₂O. The separated organic layer was washed with brine, dried(MgSO₄) and filtered. The filtrate was concentrated in vacuo and theresulting residue was purified by chromatography on silica gel elutedwith 4:1 hexanes/ethyl acetate to provide the title compound.

Example 28H4′-((1S,2R)-2-{2-[(2R)-2-Methylpyrrolidin-1-yl]ethyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrile

To a solution of the mesylate from Example 28G (methanesulfonic acid,2-[(1R,2S)-2-(4′-cyano-biphenyl-4-yl)-cyclopropyl]-ethyl ester) andpotassium carbonate in DMF was added (R)-2-methylpyrrolidinehydrobromide [CAS 117607-13-3]. The mixture was stirred at 50° C.overnight. The mixture was partitioned between ethyl acetate and H₂O.The organic layer was washed with brine, dried (MgSO₄), and concentratedin vacuo. The resulting residue was purified by chromatography on silicagel eluted with 7.5/20/70 MeOH/EtOAc/CH₂Cl₂ to provide the titlecompound. ¹H NMR (300 MHz, CDCl₃, free base): δ 0.88-1.0 (m, 2H), 1.18(d, J=6 Hz, 3H), 1.4-2.4 (m, 11H), 2.9 (m, 1H), 3.15-3.23 (m, 1H), 7.15(d, J=9 Hz, 2H), 7.47 (d, J=9 Hz, 2H), 7.66 (q, J=9 Hz, 4H). MS(DCl—NH₃) m/z 331.2 (M+H)⁺. Anal, Calc. for C₂₃H₂₆N₂.C₄H₆O₆ 1.25H₂O(L-tartaric acid salt): C, 64.46; H, 6.91; N, 5.57. Found: C, 64.46; H,6.91; N, 5.57.

Example 294′-((1R,2S)-2-{2-[(2R)-2-Methylpyrrolidin-1-yl]ethyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrileExample 29A 3-(4-Bromophenyl)-N-methoxy-N-methylacrylamide

A solution of oxalyl chloride in dichloromethane (2 M, 100 mL, 200 mmol)was added dropwise to a stirred solution of trans-4-bromocinnamic acid[CAS 1200-07-3] (25.0 g, 110 mmol) and DMF (0.5 mL) in dichloromethane(300 mL) at 0° C. under a dry nitrogen atmosphere. The nitrogen line andcooling bath were removed and the mixture was stirred at roomtemperature until gas evolution had ceased. Volatiles were removed underreduced pressure, and the residue was redissolved in dichloromethane(200 mL). The resulting solution was added dropwise to a stirredsolution of N,O-dimethylhydroxylamine hydrochloride (21.5 g, 220 mmol)and triethylamine (61.4 mL, 440 mmol) in dichloromethane (150 mL) at 0°C. When the addition was complete, the cooling bath was removed and themixture was stirred overnight at room temperature. Insoluble materialwas removed by filtration and the filtrate was concentrated underreduced pressure. The residue was partitioned between ethyl acetate andaqueous 10% citric acid, The organic layer was successively washed withaqueous 10% citric acid, aqueous 3 N sodium hydroxide, and brine. Theethyl acetate solution was then dried (MgSO₄) and filtered. The filtratewas concentrated under reduced pressure, and the residue was purified bycolumn chromatography (65:35 hexane/ethyl acetate) to provide the titlecompound. ¹H NMR (300 MHz, CDCl₃): δ 3.31 (s, 3H), 3.76 (s, 3H), 7.02(d, J=15 Hz, 1H), 7.43 (d, J=9 Hz, 2H), 7.51 (d, J=9 Hz, 2H), 7.67 (d,J=9 Hz, 1H), MS (DCl—NH₃) m/z 270 (M+H)⁺, m/z 287 (M+NH₄)⁺.

Example 29B 2-(4-Bromo-phenyl)-trans-cyclopropanecarboxylic acid,N-methoxy-N-methyl-amide (racemic)

A stirred solution of trimethylsulfoxonium iodide (26.78 g, 119 mmol) inDMSO (100 mL) at 0° C. was treated with sodium hydride (60% oildispersion, 4.57 g, 114 mmol) in small portions. When the addition wascomplete, the ice bath was removed and the mixture was stirred at roomtemperature for 45 minutes. A solution of the alkene intermediate fromExample 29A (26.85 g, 99 mmol) in DMSO (100 mL) was added dropwise tothe mixture and stirring was continued overnight. The mixture wasdiluted with saturated aqueous ammonium chloride and the mixture wasextracted with diethyl ether (4×100 mL). The combined extracts weredried (MgSO₄) and filtered. The filtrate was concentrated under reducedpressure to provide an oil that was purified by column chromatography(70:30 hexane/ethyl acetate) to provide the title compound ¹H NMR (300MHz, CDCl₃): δ 1.23-1.31 (m, 1H), 1.60-1.67 (m, 1H), 2.32-2.42 (m, 1H),2.42-2.50 (m, 1H), 3.23 (s, 3H), 3.69 (s, 3H), 7.00 (d, J=9 Hz, 2H),7.39 (d, J=9 Hz, 2H), MS (DCl—NH₃) m/z 284 (M+H)⁺, m/z 301 (M+NH₄)⁺.

Example 29C 2-(4-Bromo-phenyl)-trans-cyclopropanecarboxylic acid(racemic)

A solution of the product from Example 29B (24.3 g, 86 mmol) andpotassium t-butoxide (80.8 g, 684 mmol) in diethyl ether (900 mL) andwater (10 mL) was stirred at room temperature for three days. Themixture was then slowly acidified by the addition of concentratedhydrochloric acid. The ether layer was washed with brine and the acidicaqueous layer was extracted with ethyl acetate (2×100 mL). The etherlayer and the ethyl acetate extracts were combined, dried (MgSO₄), andfiltered. The filtrate was concentrated under reduced pressure toprovide the title compound. ¹H NMR (300 MHz, CDCl₃): δ 1.33-1.42 (m,1H), 1.63-1.71 (m, 1H), 1.84-1.91 (m, 1H), 2.51-2.60 (m, 1H), 6.98 (d,J=9 Hz, 2H), 7.41 (d, J=9 Hz, 2H), 11.08 (br s, 1H), MS (DCl—NH₃) m/z258 (M+NH₄)⁺.

Example 29D[(1R,2R)-2-(4-Bromophenyl)cyclopropyl]-{(1S,5R,7R)-(10,10-dimethyl-3,3-dioxo-3λ⁶-thia-4-azatricyclo[5.2.1.0¹⁵]dec-4-yl)}methanoneand[(1S,2S)-2-(4-Bromophenyl)cyclopropyl]-{(1S,5R,7R)-(10,10-dimethyl-3,3-dioxo-3λ⁶-thia-4-azatricyclo[5.2.1.0¹⁵]dec-4-yl)}methanone

A stirred solution of the racemic, trans-cyclopropyl intermediate inExample 29C (20.5 g, 85 mmol) in DMF (100 mL) was treated with1,1′-carbonyldiimidazole (15.2 g, 94 mmol) under a dry nitrogenatmosphere. The mixture was stirred at 40° C. for 1 hour and then(1S)-(−)-2,10-camphorsultam ([CAS 94594-90-8], Aldrich catalog number29,835-2) (25.82 g, 120 mmol) and DBU (12.7 mL, 85 mmol) were added. Themixture was stirred at 40° C. for 6 hours and then at room temperatureovernight. The mixture was then partitioned between ethyl acetate andaqueous 2 N hydrochloric acid. The organic layer was washed withsaturated aqueous sodium bicarbonate and then with brine. The ethylacetate solution was then dried (MgSO₄), and filtered. The filtrate wasconcentrated under reduced pressure, and the residue was purified bycolumn chromatography (90:5:5 hexane/dichloromethane/isopropanol).Drying under high vacuum supplied a mixture of diastereomers. Thediastereomers were separated by elution through a chiral column(Chiralcel OJ®, 90:10 hexane/ethanol). The first diastereomer to elute(retention time 11.8 minutes) was identified by x-ray crystallography aspossessing the S,S absolute configuration at the cyclopropyl carbons.The later-eluting diastereomer (retention time: 19 minutes was assignedthe R, R absolute configuration at the cyclopropyl carbons.

Early-eluting diastereomer (S,S-cyclopropyl),[(1S,2S)-2-(4-bromophenyl)cyclopropyl]-{(1S,5R,7R)-(10,10-dimethyl-3,3-dioxo-3λ⁶-thia-4-azatricyclo[5.2.1.0¹⁵]dec-4-yl)}methanone.¹H NMR (300 MHz, CDCl₃): δ 0.97 (s, 3H), 1.17 (s, 3H), 1.30-1.47 (m,3H), 1.61-1.69 (m, 1H), 1.83-1.99 (m, 3H), 2.01-2.19 (m, 2H), 2.53-2.61(m, 1H), 2.63-2.71 (m, 1H), 3.42-3.56 (m, 2H), 3.86-3.92 (m, 1H), 7.10(d, J=9 Hz, 2H), 7.40 (d, J=9 Hz, 2H). MS (DCl—NH₃) m/z 455 (M+NH₄)⁺.

Late-eluting diastereomer (R, R-cyclopropyl),[(1R,2R)-2-(4-bromophenyl)cyclopropyl]-{(1S,5R,7R)-(10,10-dimethyl-3,3-dioxo-3λ⁶-thia-4-azatricyclo[5.2.1.0¹⁵]dec-4-yl)}methanone;¹H NMR (300 MHz, CDC₃): δ 0.98 (s, 3H), 1.20 (s, 3H), 1.29-1.47 (m, 3H),1.1.73-1.83 (m, 1H), 1.83-2.00 (m, 3H), 2.00-2.18 (m, 2H), 2.46-2.59 (m,2H), 3.39-3.56 (m, 2H), 3.86-4.96 (m, 1H), 7.09 (d, J=9 Hz, 2H), 7.39(d, J=9 Hz, 2H). MS (DCl—NH₃) m/z 455 (M+NH₄)⁺.

Example 29E (1R,2R)-2-(4-Bromophenyl)cyclopropanecarbaldehyde

A solution of the later-eluting, R, R-diastereomer([(1R,2R)-2-(4-bromophenyl)cyclopropyl]-{(1S,5R,7R)-(10,10-dimethyl-3,3-dioxo-3λ⁶-thia-4-azatricyclo[5.2.1.0¹⁵]dec-4-yl)}methanone)described in Example 29D (5.2 g, 11.86 mmol) in dichloromethane (100 mL)was stirred under a dry nitrogen atmosphere at −78° C. A 1 M solution ofdiisobutylaluminum hydride in dichloromethane (26.1 mL, 26.1 mmol) wasadded dropwise to the mixture. When the addition was complete, themixture was stirred at −78° C. for 3 hour. Methanol (27 mL) was thenadded dropwise at −78° C. The dry ice bath was then replaced with an icewater bath and saturated aqueous ammonium chloride was added to quenchthe mixture. After 10 minutes, the insoluble material was removed byfiltration and the organic layer was isolated, dried (MgSO₄), andfiltered. The filtrate was concentrated under reduced pressure toprovide a colorless oil that was purified by column chromatography (9:1hexane/ethyl acetate). Fractions containing product were combined andconcentrated under reduced pressure to provide the title compound ¹H NMR(300 MHz, CDCl₃): δ 1.45-1.57 (m, 1H), 1.70-1.78 (m, 1H), 2.11-2.19 (m,1H), 2.55-2.63 (m, 1H), 6.99 (d, J=9 Hz, 2H), 7.42 (d, J=9 Hz, 2H), 9.35(d, J=45 Hz, 1H) MS (DCl—NH₃) m/z 225 (M+H)⁺¹, m/z 242 (M+NH₄)⁺.

Example 29F 1-Bromo-4-[1R,2S)-2-vinyl-cycloprop-1-yl]benzene

The aldehyde intermediate from Example 29E (2.35 g, 10.44 mmol) wasconverted to the alkene by the methods outlined in Example 26E, followedby chromatography (100% hexane) provided the title compound ¹H NMR (300MHz, CDCl₃): δ 1.07-1.19 (m, 2H), 1.60-1.71 (m, 1H) 1.83-1.91 (m, 1H),4.91-4.97 (m, 1H), 5.05-5.14 (m, 1H), 5.45-5.59 (m, 1H), 6.93 (d, J=9Hz, 2H), 7.36 (d, J=9 Hz, 2H). MS (DCl—NH₃) m/z 241 (M+NH₄)⁺.

Example 29G 2-[(1S,2R)-2-(4-Bromophenyl)cycloprop-1-yl]ethanol

The alkene intermediate from Example 29F (1.64 g, 7.35 mmol) wasconverted to the alcohol by the method of Example 26F, followed bychromatography (7.3 hexane/ethyl acetate) provided the title compound.¹H NMR (300 MHz, CDCl₃): δ 0.96-0.79 (m, 2H), 1.00-1.14 (m, 1H),1.54-1.76 (m, 3H), 4.91-4.97 (m, 1H), 3.76 (t, J=6 Hz, 2H), 6.92 (d, J=9Hz, 2H), 7.35 (d, J=9 Hz, 2H). MS (DCl—NH₃) m/z 258 (M+NH₄)⁺.

Example 29H4′-[91R,2S)-2-(2-Hydroxyethyl)cycloprop-1-yl]biphenyl-4-carbonitrile

The bromophenyl intermediate from Example 29G (0.83 g, 3.44 mmol) wasconverted to the biphenyl intermediate by the method of Example 26G, butwith a total reaction time of 45 minutes, followed by chromatography(7.3 hexane/ethyl acetate) provided the title compound. ¹H NMR (300 MHz,CDCl₃): δ 0.87-0.95 (m, 1H), 0.97-1.04 (m, 1H), 1.11-1.24 (m, 1H),1.61-1.79 (m, 3H), 3.79 (t, J=6 Hz, 2H), 7.15 (d, J=9 Hz, 2H), 7.48 (d,J=9 Hz, 2H), 7.67 (q, J=9 Hz, 4H). MS (DCl—NH₃) m/z 281 (M+NH₄)⁺.

Example 29I Methanesulfonic acid,2-[(1S,2R)-2-(4′-cyano-biphenyl-4-yl)-cyclopropyl]-ethyl ester

The alcohol intermediate from Example 29H (0.31 g, 1.18 mmol) wasconverted to the mesylate intermediate by the method of Example 26H toprovide the title compound. ¹H NMR (300 MHz, CDCl₃): δ 0.89-0.96 (m,1H), 1.00-1.08 (m, 1H), 1.13-1.24 (m, 1H), 1.76-1.93 (m, 3H), 2.98 (s,3H), 4.35 (t, J==6 Hz, 2H), 7.16 (d, J=9 Hz, 2H), 7.49 (d, J=9 Hz, 2H),7.68 (q, J=9 Hz, 4H) MS (DCl—NH₃) m/z 359 (M+NH₄)⁺.

Example 29J4′-((1R,2S)-2-{2-[(2R)-2-Methylpyrrolidin-1-yl]ethyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrile

The mesylate intermediate from Example 29I (0.37 g, 1.08 mmol) wasconverted to the final product by the method of Example 26I. The titlecompound was obtained after column chromatography (95:5:tracedichloromethane/methanol/ammonium hydroxide). The title compound wasdissolved in methanol. To this stirred solution was added a solution ofone equivalent of L-tartaric acid in methanol. After stirring for 15minutes, the solution was concentrated to half volume and treated withethyl ether to induce crystallization of the title compound as the monoL-tartaric acid salt, ¹H NMR (300 MHz, CD₃OD, L-tartaric acid salt). δ0.93-1.10 (m, 2H), 1.13-1.24 (m, 1H), 1.44 (d, J=6 Hz, 3H), 1.71-1.85(m, 2H), 1.85-1.99 (m, 2H), 2.02-2.15 (m, 2H), 2.25-2.49 (m, 1H),3.06-3.19 (m, 2H), 3.41-3.56 (m, 2H), 3.59-3.72 (m, 1H), 4.39 (s, 2H),7.21 (d, J=9 Hz, 2H), 7.58 (d, J=9 Hz, 2H), 7.77 (s, 4H). MS (DCl—NH₃)m/z 331 (M+H)⁺.

Example 304′-((1S,2R)-2-{2-[(2R)-2-Methylpyrrolidin-1-yl]ethyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrileExample 30A (1S,2S)-2-(4-Bromophenyl)cyclopropanecarbaldehyde

A solution of the early-eluting, S,S-diastereomer([(1S,2S)-2-(4-bromophenyl)cyclopropyl]-{(1S,5R,7R)-(10,10-dimethyl-3,3-dioxo-3λ⁶-thia-4-azatricyclo[5.2.1.0¹⁵]dec-4-yl)}methanone)described in Example 29D in dichloromethane was stirred under a drynitrogen atmosphere at −78° C. A 1 M solution of diisobutylaluminumhydride in dichloromethane was added dropwise to the mixture. When theaddition was complete, the mixture was stirred at −78° C. for 3 hours.Methanol was then added dropwise at −78° C. The dry ice bath was thenreplaced with an ice water bath and saturated aqueous ammonium chloridewas added to quench the mixture. After 10 minutes, the insolublematerial was removed by filtration and the organic layer was separated,dried (MgSO₄), and filtered. The filtrate was concentrated under reducedpressure, and the residue was purified by column chromatography (9:1hexane/ethyl acetate). Fractions containing product were combined andconcentrated under reduced pressure to provide the title compound.

Example 30B 1-Bromo-4-[(1S,2R)-2-vinyl-cycloprop-1-yl]benzene

The product from Example 30A was subjected to the conditions outlined inin Example 26E, followed by chromatography (100% hexane) to provide thetitle compound.

Example 30C 2-[(1R,2S)-2-(4-Bromophenyl)cycloprop-1-yl]ethanol

The product from Example 30B was subjected to the conditions outlined inExample 26F, followed by chromatography (7:3 hexane/ethyl acetate) toprovide the title compound

Example 30D4′-[(1S,2R)-2-(2-Hydroxyethyl)cycloprop-1-yl]biphenyl-4-carbonitrile

The product from Example 30C was subjected to the conditions outline inExample 26G, followed by chromatography (7:3 hexane/ethyl acetate) toprovide the title compound,

Example 30E Methanesulfonic acid,2-[(1R,2S)-2-(4′-cyano-biphenyl-4-yl)-cyclopropyl]-ethyl ester

The product from Example 30D was subjected to the conditions outlined inExample 26H to provide the title compound.

Example 30F4′-((1S,2R)-2-{2-[(2R)-2-methylpyrrolidin-1-yl]ethyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrile

The product from Example 30E (methanesulfonic acid,2-[(1R,2S)-2-(4′-cyano-biphenyl-4-yl)-cyclopropyl]-ethyl ester), 0.40 g,1.17 mmol) was further converted to4′-((1S,2R)-2-{2-[(2R)-2-methylpyrrolidin-1-yl]ethyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrilethrough the procedure described in Example 29J Column chromatography(96.4:trace dichloromethane/methanol/ammonium hydroxide) provided thetitle compound. The title compound was dissolved in ethyl ether andanhydrous HCl gas was bubbled into the solution to provide thehydrochloride salt of the title compound that was crystallized frommethanol/ethyl ether. ¹H NMR (300 MHz, CD₃OD, hydrochloride salt): δ0.95-1.12 (m, 2H), 1.14-1.24 (m, 1H), 1.45 (d, J=6 Hz, 3H), 1.66-1.81(m, 1H), 1.81-1.93 (m, 3H), 2.00-2.17 (m, 2H), 2.27-2.41 (m, 1H),3.07-3.26 (m, 2H), 3.43-356 (m, 2H), 3.64-3.75 (m, 1H), 7.21 (d, J=9 Hz,2H), 7.58 (d, J=9 Hz, 2H), 7.77 (s, 4H). MS (DCl—NH₃) m/z 331 (M+H)⁺.

Example 314′-[(trans)-2-(2-Pyrrolidin-1-ylethyl)cyclopropyl]-1,1′-biphenyl-4-carbonitrileExample 31A tert-Butyl(but-3-ynyloxy)dimethylsilane

A stirred, 0° C. solution of homopropargyl alcohol (10 g, 0.14 mol) andtert-butyldimethylsilyl chloride (21.5 g, 0.14 mol) in dichloromethane(50 mL) was treated with triethylamine (22.8 mL, 0.168 mol). The mixturewas then stirred overnight at room temperature. The mixture was washedwith water and the organic layer was dried (MgSO₄) and filtered. Thefiltrate was concentrated under reduced pressure, and the residue waspurified by chromatography (95:5 hexane/ethyl acetate) to provide thetitle compound. ¹H NMR (300 MHz, CDCl₃): δ 0.08 (s, 6H), 0.90 (s, 9H),1.96 (t, J=3 Hz, 1H), 2.41 (dt, J=6 Hz, J=3 Hz, 2H), 3.75 (d, J=6 Hz,2H).

Example 31BTert-butyl-dimethyl-(4-tributylstannanyl-but-3-enyloxy)-silane

A solution of Example 31A (1.08 g, 5687 mmol), tri-(n-butyl)tin hydride(1.43 mL, 5.31 mmol), and AIBN (cat.) in benzene (10 mL) was stirred at80° C. for 3 hours. Volatiles were removed under reduced pressure toprovide the title compound as a colorless oil (>95% E-isomer). ¹H NMR(300 MHz, CDCl₃): δ 0.05 (s, 6H), 0.80-0.98 (m, 15H), 0.90 (s, 9H),1.23-1.38 (m, 6H), 1.42-1.53 (m, 6H), 2.34-2.40 (m, 2H), 3.66 (d, J=6Hz, 2H), 5.94-5.98 (m, 2H).

Example 31C4′-[4-(Tert-butyl-dimethyl-silanyloxy)-but-1-enyl]-biphenyl-4-carbonitrile

A solution of Example 31B (4.95 g, 10.4 mmol), 4′-cyanobiphenyl triflate(3.1 g, 9.48 mmol, prepared from 4′-hydroxybiphenyl-4-carbonitrile bystandard methods), and Pd(PPh₃)₂Cl₂ (0.332 g, 0.47 mmol) in DMF (20 mL)was stirred at 80° C. overnight. The mixture was cooled to roomtemperature and partitioned between ethyl acetate and water. The organiclayer was dried (MgSO₄) and filtered. The filtrate was concentratedunder reduced pressure and the residue was purified by columnchromatography (97.5:2.5 hexane/ethyl acetate) to provide the titlecompound, ¹H NMR (300 MHz, CDCl₃): δ 0.07 (s, 6H), 0.91 (s, 9H), 2.46(q, J=6 Hz, 2H), 3.75 (t, J=6 Hz, 2H), 6.32 (d, J=16 Hz, 1H), 6.48 (d,J=16 Hz, 1H), 7.44 (d, J=9 Hz, 2H), 7.54 (d, J=9 Hz, 2H), 7.65-7.74 (m,4H) MS (DCl—NH₃) m/z 364 (M+H)⁺, m/z 359 (M+NH₄)⁺

Example 31DTrans-4′{2-[2-(tert-butydimethylsilanyloxy)ethyl]cyclopropyl}biphenyl-4-carbonitrile(racemic)

The cyclopropanation reaction was conducted according to the procedurein Tetrahedron Letters 1998, 39, 8621-8624. A stirred solution ofdiethyl zinc (1 M in hexane, 4.1 mL, 4.1 mmol) in dichloromethane (10mL) was chilled to 0° C. A solution of trifluoroacetic acid (0.32 mL,4.1 mmol) in dichloromethane (2 mL) was added dropwise to the coldmixture. Stirring at 0° C. was continued for 20 minutes, and then asolution of diiodomethane (0.4 mL, 4.9 mmol) in dichloromethane (2 mL)was added dropwise to the cold mixture. After 20 minutes, a solution ofExample 31C (0.6 g, 1.65 mmol) in dichloromethane (5 mL) was added tothe mixture and the ice bath was removed. The mixture was stirred atroom temperature for 3 hours, diluted with 0.1 N aqueous HCl andextracted with hexane. The crude product was purified by preparativethin layer chromatography (97:3 hexane/ethyl acetate) to provide thetitle compound. ¹H NMR (300 MHz, CDCl₃): δ 0.04 (s, 3H), 0.05 (s, 3H),0.84-0.97 (m, 2H), 0.89 (s 3H), 1.56-1.75 (m, 3H), 3.74 (t, J=6 Hz, 2H),7.14 (d, J=9 Hz, 2H), 7.48 (d, J=9 Hz, 2H), 7.65 (d, J=9 Hz, 2H), 7.71(d, J=9 Hz, 2H), MS (DCl—NH₃) m/z 378 (M+H)⁺, m/z 359 (M+NH₄)⁺

Example 31ETrans-4′-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-cyclopropyl}-biphenyl-4-carbonitrile(racemic)

A 1 M solution of tetrabutylammonium fluoride in THF (3.1 mL, 3.1 mmol)was added to a stirred, room temperature solution of Example 31D (0.585g, 1.55 mmol) in THF (5 mL). The mixture was stirred for 2 hours,partitioned between ethyl acetate and water. The organic layer was dried(MgSO₄) and filtered. The filtrate was concentrated under reducedpressure, and the residue was purified by column chromatography (65:35hexane/ethyl acetate) to provide the title compound. ¹H NMR (300 MHz,CDCl₃): δ 0.87-0.97 (m, 1H), 0.97-1.05 (m, 1H), 1.12-1.21 (m, 1H),1.64-1.79 (m, 2H), 3.76-3.84 (m, 2H), 7.15 (d, J=9 Hz, 2H), 7.48 (d, J=9Hz, 2H), 7.68 (q, J=9 Hz, 4H) MS (DCl—NH₃) m/z 281 (M+H)⁺.

Example 31F Methanesulfonic acid,trans-2-[2-(4′-cyano-biphenyl-4-yl)-cyclopropyl]-ethyl ester (racemic)

Triethylamine (0.18 mL, 1.29 mmol) was added to a stirred, roomtemperature solution of Example 31E (0.24 g, 0.91 mmol) andmethanesulfonyl chloride (0.092 mL, 1.19 mmol) in dichloromethane (10mL). After stirring for 30 minutes, the mixture was washed with water.The organic layer was dried (MgSO₄), and filtered. The filtrate wasconcentrated under reduced pressure to provide the crude title compound.¹H NMR (300 MHz, CDCl₃): δ 0.89-0.96 (m, 1H), 1.01-1.08 (m, 1H),1.13-1.23 (m, 1H), 1.76-1.83 (m, 1H), 1.83-1.93 (m, 2H), 2.99 (s, 3H),4.35 (t, J=6 Hz, 2H), 7.16 (d, J=9 Hz, 2H), 749 (d, J=9 Hz, 2H), 7.68(q, J=9 Hz, 4H). MS (DCl—NH₃) m/z 359 (M+NH₄)⁺.

Example 31G4′-[(trans)-2-(2-Pyrrolidin-1-yethyl)cyclopropyl]-1,1′-biphenyl-4-carbonitrile

A solution of Example 31F (0.054 g, 0.158 mmol) in pyrrolidine (5 mL)was stirred at reflux overnight. Volatiles were removed under reducedpressure, and the residue was purified by column chromatography (95:5dichloromethane/methanol) to provide the title compound ¹H NMR (300 MHz,CDCl₃): δ 0.84-0.91 (m, 1H), 0.92-1.0 (m, 1H), 1.05-1.16 (m, 1H),1.5-1.9 (m, 8H), 2.48-2.75 (m, 5H), 7.14 (d, J=9 Hz, 2H), 7.48 (d, J=9Hz, 2H), 7.65 (q, J=9 Hz, 4H). MS (DCl—NH₃) m/z 317 (M+H)⁺.

Example 32N-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]-5-(trifluoromethyl)thieno[3,2-b]pyridine-6-carboxamideExample 32A4-((1S,2S)-2-(((S)-2-methylpyrrolidin-1-yl)methyl)cyclopropyl)aniline

A solution of the product from Example 1D (1.72 g, 5.85 mmol), lithiumbis(trimethylsilyl)amide (1.51 g, 8.78 mmol), Pd₂(dba)₃ (268 mg, 0.29mmol) and tri-t-butylphosphine (1.42 g, 10% in hexane, 0.702 mmol) inanhydrous toluene (10 mL) was heated to 120° C. in a sealed tube for 16hours. The mixture was cooled to ambient temperature, treated with HCl(1 M) and extracted with ethyl acetate (2×75 mL). The organic layerswere combined, washed with H₂O and brine, and dried with magnesiumsulfate. After filtration, the organic layer was concentrated underreduced pressure and the resulting oil was purified on silica gel with1% to 3% methanol (containing 10% concentrated NH₄OH) in dichloromethaneto provide the title compound. ¹H NMR (300 MHz, CD₃OD) δ 0.70-0.76 (m,1H), 0.82-0.88 (m, 1H), 1.13 (d, J=6 Hz, 3H), 1.03-1.11 (m, 1H),1.35-1.48 (m, 1H), 1.60-1.66 (m, 1H), 1.69-1.87 (m, 3H), 1.92-2.04 (m,1H), 2.27 (dd, J=12 Hz, J=9 Hz, 1H), 2.32-2.40 (m, 1H), 3.12 (dd, J=12Hz, J=3 Hz, 1H), 3.23-3.29 (m, 1H), 6.64 (d, J=9 Hz, 2H), 6.84 (d, J=9Hz, 2H). MS (DCl—NH₃) m/z 231 (M+H)⁺.

Example 32BN-[4-(1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]-5-(trifluoromethyl)thieno[3,2-b]pyridine-6-carboxamide

A solution of the product from Example 32A (50 mg, 0.22 mmol),5-(trifluoromethyl)thieno[3,2-b]pyridine-6-carboxylic acid (110 mg, 0.44mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride(55 mg, 0.28 mmol) in DCM (10 mL) was treated with triethylamine (0.061mL, 0.44 mmol), and stirred at ambient temperature for 16 hours. Themixture was concentrated under reduced pressure and the residue waspurified on silica gel with 1% to 3% methanol (containing 10%concentrated NH₄OH) in dichloromethane to provide the title compound. ¹HNMR (300 MHz, CD₃OD) δ 0.86-1.92 (m, 1H), 0.99-1.05 (m, 1H), 1.17 (d,J=6 Hz, 3H), 1.20-1.29 (m, 1H), 1.42-1.52 (m, 1H), −1.73-1.83 (m, 3H),1.94-2.08 (m, 2H), 2.32-2.51 (m, 2H), 3.17 (dd, J=12 Hz, J=3 Hz, 1H),3.26-3.30 (m, 1H), 7.10 (d, J=9 Hz, 1H), 7.55 (d, J=9 Hz, 2H), 7.70 (d,J=6 Hz, 2H), 8.30 (d, J=6 Hz, 1H), 8.74 (s, 1H). MS (DCl—NH₃) m/z 460(M+H)⁺.

Example 33N-(4-[(1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl]phenyl)isonicotinamide

A solution of the product from Example 32A (50 mg, 0.22 mmol);isonicotinoyl chloride hydrochloride (62 mg, 0.31 mmol), and4-dimethylaminopyridine (5 mg, 0.04 mmol) in DCM (10 mL) was treatedwith triethylamine (0.12 mL, 0.86 mmol) and stirred at ambienttemperature for 16 hours. The mixture was concentrated under reducedpressure and the residue was purified on silica gel with 1% to 3%methanol (containing 10% concentrated NH₄OH) in dichloromethane toprovide the title compound. ¹H NMR (300 MHz, CD₃OD) δ 1.04-1.10 (m, 1H),1.16-1.23 (m, 1H), 1.39 (d, J=6 Hz, 3H), 1.37-1.42 (m, 1H), 1.66-1.77(m, 1H), 2.01-2.08 (m, 3H), 2.25-2.36 (m, 1H), 2.94 (dd, J=6 Hz, J=3 Hz,1H), 3.15-3.21 (m, 1H), 3.40 (dd, J=6 Hz, J=3 Hz, 1H), 3.61-3.70 (m,1H), 7.16 (d, J=9 Hz, 1H), 7.63 (d, J=9 Hz, 2H), 7.86 (d, J=6 Hz, 2H),8.73 (d, J=3 Hz, 1H), 8.03 (m, 1H). MS (DCl—NH₃) m/z 336 (M+H)⁺.

Example 342-[4-((1S,2S)-2-{[(2S)-2-Methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-oneExample 34A (E)-3-(4-bromophenyl)prop-2-en-1-ol

To a solution of (E)-ethyl 3-(4-bromophenyl)acrylate (25 g, 96 mmol) inDCM (300 ml) under nitrogen and cooled to −78° C. was added dropwiseDIBAL-H (240 ml, 1M in DCM, 240 mmol) in about 20 minutes. The mixturewas stirred at 78° C. for 2 hours. Then, the dry ice bath was removed.The reaction was diluted with DCM (500 mL), quenched with HCl (1N), andpartitioned. The combined organic phases were washed with H₂O, dried andconcentrated under reduced pressure to provide the title compound. ¹HNMR (300 MHz, CDCl₃):

1.43 (t, J=6 Hz, 1H), 4.32 (t, J=4.5 Hz, 2H), 6.37 (dt, J=16.5 Hz, J=6Hz, 1H), 6.57 (d, J=15 Hz, 1H), 7.25 (d, J=9 Hz, 2H), 7.45 (d, J=9 Hz,2H). MS (DCl—NH₃) m/z 214 (M+H)⁺.

Example 34B 2-butyl-1,3,6,2-dioxazaborocane

To a solution of 2,2′-azanediyldiethanol (26.12 g, 246 mmol) in DCM (250ml) and ether (500 mL) was added n-butylboronic acid (25.4 g, 242 mmol)and molecular sieves (3 A, 4-6 mesh, 65 g). It was stirred at ambienttemperature for 2 hours. The mixture was filtered, and the filtrate wasconcentrated under reduced pressure. The resulting white solid wasrecrystallized with DCM/ether to provide white crystals as the titleproduct. NMR (300 MHz, CDCl₃):

0.47 (t, J=9 Hz, 2H), 0.88 (t, J=6 Hz, 3H), 1.20-1.37 (m, 4H), 2.82 (br,2H), 3.24 (br, 2H), 3.95 (br, 4H), 4.27 (br, 1H). MS (DCl—NH₃) m/z 172(M+H)⁺.

Example 34C(4R,5R)-2-butyl-N4,N4,N5,N5-tetramethyl-1,3,2-dioxaborolane-4,5-dicarboxamide

A solution of the product from Example 34B (31.3 g, 183 mmol) and(2R,3R)-2,3-dihydroxy-N1,N1,N4,N4-tetramethylsuccinamide (31 g, 149mmol) in DCM (600 mL) was treated with brine (120 mL) and stirred atambient temperature for 30 minutes. The organic layer was separated, andthe aqueous layer was extracted with additional DCM. The organic layerswere combined and washed with brine (700 mL), dried with MgSO₄, andconcentrated under reduced pressure to provide the title product. NMR(300 MHz, CDCl₃):

0.83-0.90 (m, 6H), 1.26-1.42 (m, 5H), 2.98 (s, 6H), 3.20 (s, 6H) MS(DCl—NH₃) m/z 205 (M+H)⁺.

Example 34D (1S,2S)-[2-(4-Bromophenyl)cyclopropyl]methanol

A solution of DME (24.39 mL, 235 mmol) in DCM (700 mL) under nitrogenatmosphere was cooled to −10° C., and diethylzinc (235 mL, 1M in hexane,235 mmol) was added over 5-10 minutes followed by diiodomethane (37.9mL, 469 mmol). The product from Example 34C (33.0 g, 122 mmol) in 100 mLDCM was added in 5-10 minutes. The temperature was maintained from −5°to −10° C. throughout the additions. The product from Example 34A,(E)-3-(4-bromophenyl)prop-2-en-1-ol (20 g, 94 mmol) in DCM (150 mL) wasadded dropwise, and the reaction mixture was stirred at ambienttemperature for 16 hours. It was quenched with saturated aqueous NH₄Cl(300 mL), HCl (1N, 480 mL) and diluted with ether (900 mL). The organiclayer was separated. The aqueous layer was extracted with additionalether. The organic layers were is combined and treated with NaOH (2N,880 mL) To the solution, H₂O₂ (30%, 136 mL) was added dropwise while thereaction was cooled with an ice bath. The solution was stirred for 5-10minutes. The organic layer was separated, washed with HCl (1N),saturated aqueous Na₂S₂O₃, saturated aqueous NaHCO₃, and brine, driedand concentrated. The residue was chromatographed on silica gel elatingwith 5-15% EtOAc/Hexane to provide the title compound. ¹H NMR (300 MHz,CDCl₃): δ 0.92-1.0 (m, 2H), 1.45-1.48 (m, 2H), 1.76-1.85 (m, 1H), 3.61(d, J=7.5 Hz, 2H), 6.95 (d, J=9 Hz, 2H), 7.37 (d, J=9 Hz, 2H). MS(DCl—NH₃) m/z 228 (M+H)⁺. (ee 94%).

Example 34E (1S,2S)-2-(4-Bromophenyl)cyclopropanecarbaldehyde

To a solution of oxalyl chloride (17.50 mL, 2 M in DCM, 35.0 mmol) inDCM (150 mL) under nitrogen atmosphere and cooled to −78° C. was addeddrop wise DMSO (4.97 mL, 70.0 mmol), followed with the dropwise additionof a solution of the product from Example 34D,((1S,2S)-2-(4-bromophenyl)cyclopropyl)methanol (5.3 g, 23.34 mmol) inDCM (100 mL). The mixture was stirred 30 minutes at −78° C. Then themixture was treated with triethylamine (13.01 mL, 93 mmol), and then thereaction temperature was raised to ambient temperature. The mixture waspartitioned between DCM (400 mL) and H₂0 (400 mL). The organic layer wasseparated, washed with water, dried and concentrated under reducedpressure to provide the title product. ¹H NMR (300 MHz, CDCl₃): δ 1.48(m, 1H), 1.65 (dt, J=9 Hz, J=6 Hz, 1H), 2.15 (m, 1H), 2.57 (m, 1H), 6.98(d, J=9 Hz, 2H), 7.45 (d, J=9 Hz, 2H), 9.46 (d, J=4.5 Hz, 1H). MS(DCl—NH₃) m/z 226 (M+H)⁺.

Example 34F 1{[(1S,2S)-2-(4-bromophenylcyclopropyl]methyl}-(2S)-2-methylpyrrolidine

A solution of the product from Example 34E,(1S,2S)-2-(4-bromophenyl)cyclopropanecarbaldehyde (5.7 g, 25.3 mmol) inDCM (20 ml) and MeOH (300 mL) was treated with (S)-2-methylpyrrolidinetartrate (8.94 g, 38.0 mmol) at ambient temperature, and the mixture wasstirred for 5-10 minutes. Then, the mixture was cooled to 0° C., and asolution of NaCNBH₃ (2.51 g, 38.0 is mmol) in MeOH (50 mL) was addeddropwise. After addition, the reaction mixture was raised to roomtemperature and stirred overnight. The reaction mixture was treated withNaOH (1N) till basic, extracted with DCM thrice (500 mL×3), dried andconcentrated under reduced pressure. The crude product was loaded onto asilica gel column and eluted with 1% to 3% methanol (containing 10%concentrated NH₄OH) in dichloromethane to provide the title product ¹HNMR (300 MHz, CDCl₃):

0.87-0.92 (m, 1H), 0.97-1.02 (m, 1H), 1.16 (d, J=6 Hz, 2H), 1.22 (m,1H), 1.39-1.49 (m, 1H), 1.73-1.81 (m, 3H), 2.0 (m, 2H), 2.36 (q, J=6 Hz,1H), 2.45 (m, 1H), 3.13 (dd, J=12 Hz, J=6 Hz, 1H), 3.25 (m, 1H), 7.00(d, J=6 Hz, 2H), 7.37 (d, J=6 Hz, 2H). MS (DCl—NH₃) m/z 294 (M+H)⁺.

Example 34G2-[4-((1S,2S)-2-{[(2S)-2-Methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-one

A solution of the product from Example 34F,1{[(1S,2S)-2-(4-bromophenyl)cyclopropyl]methyl}-(2S)-2-methylpyrrolidine(100 mg, 0.340 mmol), pyridazin-3(2H)-one (52.3 mg, 0.544 mmol),N1,N2-dimethylethane-1,2-diamine (0.088 mL, 0.816 mmol) and copper(I)iodide (78 mg, 0.408 mmol) in pyridine (2 mL) under a nitrogenatmosphere in a sealed vial was heated in an oil bath to 135° C. for 16hours. The reaction mixture was cooled and diluted with DCM (10 mL),filtered through diatomaceous earth and washed with DCM. The filtratewas washed sequentially with H₂O, 28-30% NH₄OH (10 mL×2), and H₂O, driedwith MgSO₄ and concentrated under reduced pressure. The residue waschromatographed on silica gel eluting with concentrated concentratedNH₄OH/MeOH/DCM (0.4/4/96) to provide the title compound. ¹H NMR (300MHz, CD₃OD), δ 0.90-0.97 (m, 1H), 1.03-1.09 (m, 1H), 1.15 (d, J=6 Hz,3H), 1.23-1.33 (m, 1H), 1.39-1.49 (m, 1H), 1.70-1.80 (m, 2H), 1.82-2.05(m, 3H), 2.26-2.42 (m, 2H), 3.16 (dd, J=12 Hz, J=6 Hz, 1H), 3.21-3.28(m, 1H), 7.07 (d, J=6 Hz, 2H), 7.21 (dd, J=6 Hz, J=1.5 Hz, 2H), 7.43 (d,J=6 Hz, 2H), 7.47 (dd, J=9 Hz, J=3 Hz, 1H), 8.02 (dd, J=6 Hz, J=1.5 Hz,1 HK) MS (DCl—NH₃) m/z 310 (M+H)⁺.

Example 34H2-[4-((1S,2S)-2-{[(2S)-2-Methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-one(2R,3R)-2,3-dihydroxysuccinate

A solution of the product from Example 34G (3.25 g, 10.5 mmol) inmethanol (20 mL) was treated with L-tartaric acid (1.577 g, 10.5 mmol)and stirred at ambient temperature for 1 hour. The mixture wasconcentrated under reduced pressure, and the resulting solid wasrecrystallized from isopropyl alcohol/acetone to provide the titledcompound as the L-tartrate. ¹H NMR (300 MHz, CD₃OD) δ 1.12-1.19 (m, 1H),1.23-1.30 (m, 1H), 1.43 (d, J=6 Hz, 3H), 1.47-1.56 (m, 1H), 1.72-1.81(m, 1H), 2.02-2.19 (m, 3H), 2.28-2.39 (m, 1H), 3.04-3.11 (m, 1H),3.43-3.55 (m, 2H), 3.64-3.75 (m, 1H), 4.38 (s, 2H), 7.08 (dd, J=6 Hz,J=2 Hz, 1H), 7.28 (d, J=6 Hz, 2H), 7.44-7.50 (m, 3H), 8.03 (m, 1H). MS(DCl—NH₃) m/z 310 (M+H)⁺. Anal Calcd. For C23H29N3O7: C, 60.12, 6.36, N,9.14. Found-60.07, 5.76; N, 8.82.

Example 352-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-oneExample 35A(R)-1-(((1S,2S)-2-(4-bromophenyl)cyclopropyl)methyl)-2-methylpyrrolidine

The title compound was prepared using the procedure described in Example34F substituting (R)-2-methylpyrrolidine tartrate for(S)-2-methylpyrrolidine tartrate, ¹H NMR (300 MHz, CDCl₃)

0.88-0.94 (m, 1H) 0.95-1.02 (m, 1H), 1.12 (d, J=6 Hz, 2H), 1.19-1.29 (m,1H), 1.37-1.49 (m, 1H), 1.71-1.81 (m, 3H), 1.93-2.05 (m, 1H), 2.12 (dd,J=12 Hz, J=6 Hz, 1H), 2.29 (q, J=6 Hz, 1H), 2.36-2.45 (m, 1H), 2.93 (dd,J=12 Hz, J=6 Hz, 1H), 3.25 (m, 1H), 7.00 (d, J=6 Hz, 2H), 7.37 (d, J=6Hz, 2H) MS (DCl—NH₃) m/z 294 (M+H)⁺.

Example 35B2-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-one

The title compound was prepared using the procedure described in Example34G substituting the product from Example 35A for the product fromExample 34F,1-{[(1S,2S)-2-(4-bromophenyl)cyclopropyl]methyl}-(2S)-2-methylpyrrolidine.¹H NMR (300 MHz, CD₃OD) δ 0.94-0.98 (m, 1H), 1.05-1.09 (m, 1H), 1.13 (d,J=3 Hz, 3H), 1.30-1.36 (m, 1H), 1.4-1.48 (m, 1H), 1.72-1.81 (m, 2H),1.84-1.88 (m, 1H), 2.16 (dd, J=6 Hz, J=3 Hz, 1H), 2.31 (q, J=6 Hz, 1H),2.41-2.45 (m, 1H), 2.94-2.98 (q, J=3 Hz, 1H), 3.25-3.29 (m, 1H), 7.07(d, J=6 Hz, 2H), 7.21 (d, J=6 Hz, 2H), 7.41 (d, J=6 Hz, 2H), 7.46 (dd,J=6 Hz, J=3 Hz, 1H), 8.02-8.03 (m, 1H). MS (DCl—NH₃) m/z 310 (M+H)⁺.

Example 361-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]piperidin-2-one

The title compound was prepared using the procedure described in Example34G substituting piperidin-2-one for pyridazin-3(2H)-one andsubstituting the product from Example 35A for the product from Example34F. ¹H NMR (300 MHz, CD₃OD) δ 1.08-1.21 (m, 2H), 1.39 (d, J=6 Hz, 3H),1.43-1.48 (m, 1H), 1.68-1.78 (m, 1H), 1.92-1.96 (m, 3H), 2.01-2.08 (m,3H), 2.23-2.35 (m, 1H), 2.50 (t, J=6 Hz, 2H), 3.03 (dd, J=12 Hz, J=6 Hz,1H), 3.13-3.22 (m, 1H), 3.32-3.36 (m, 1H), 3.39-3.47 (m, 1H), 3.58-3.67(m, 3H), 7.17 (d, J=3 Hz, 4H). MS (DCl—NH₃) m/z 313 (M+H)⁺.

Example 371-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]azepan-2-one

The title compound was prepared using the procedure described in Example35B substituting azepan-2-one for pyridazin-3(2H)-one and substitutingthe product from Example 35A for the product from Example 34F. ¹H NMR(300 MHz, CD₃OD) δ 1.02-1.08 (m, 1H), 1.13-1.19 (m, 1H), 1.36 (d, J=6Hz, 3H), 1.35-1.38 (m, 1H), 1.64-1.71 (m, 1H), 1.84 (broad, 6H),1.97-2.05 (m, 3H), 2.21-2.32 (m, 1H), 2.67-2.71 (m, 2H), 2.78-2.85 (m,1H), 3.05-3.15 (m, 1H), 3.23-3.28 (m, 1H), 3.35-3.41 (m, 1H), 3.54-3.63(m, 1H), 3.75-3.78 (m, 1H), 7.13 (d, J=3 Hz, 4H). MS (DCl—NH₃) m/z 327(M+H)⁺.

Example 381-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrrolidin-2-one

The title compound was prepared using the procedure described in Example35B substituting pyrrolidin-2-one for pyridazin-3(2H)-one andsubstituting the product from Example 35A for the product from Example34F. ¹H NMR (300 MHz, CD₃OD) δ 0.89-0.96 (m, 1H), 1.01-0.08 (m, 1H),1.22 (d, J=6 Hz, 3H), 1.25-1.30 (m, 1H), 1.48-1.55 (m, 1H), 1.8-1.89 (m,4H), 2.03-2.27 (m, 4H), 2.57 (t, J=6 Hz, 2H), 2.65-2.74 (m, 1H), 3.22(q, J=6 Hz, 1H), 3.33-3.40 (m, 1H), 3.89 (t, J=6 Hz, 2H), 7.10 (d, J=9Hz, 2H), 7.46 (d, J=9 Hz, 2H). MS (DCl—NH₃) m/z 299 (M+H)⁺.

Example 391-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]azetidin-2-one

The title compound was prepared using the procedure described in Example35B substituting azetidin-2-one for pyridazin-3(2H)-one and substitutingthe product from Example 35A for the product from Example 34F. ¹H NMR(300 MHz, CD₃OD) δ 0.98-1.04 (m, 1H), 1.08-1.15 (m, 1H), 1.34 (d, J=6Hz, 3H), 1.35 (m, 1H), 1.59-1.72 (m, 1H), 1.94-2.04 (m, 3H), 2.18-2.29(m, 1H), 2.75 (q, J=6 Hz, 1H), 2.98-3.07 (m, 1H), 3.08 (1, J=6 Hz, 2H),3.16-3.26 (m, 1H), 3.32-3.36 (m, 1H), 3.52-3.62 (m, 1H), 3.65 (t, J=6Hz, 2H), 7.11 (d, J=9 Hz, 2H), 7.30 (d, J=9 Hz, 2H). MS (DCl—NH₃) m/z299 (M+H)⁺.

Example 401-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]azetidin-2-one

The title compound was prepared using the procedure described in Example34G substituting azetidin-2-one for pyridazin-3(2H)-one, ¹H NMR (300MHz, CD₃OD) δ 0.97-1.03 (m, 1H), 1.08-1.14 (m, 1H), 1.33 (d, J=6 Hz,3H), 1.35 (m, 1H), 1.60-1.68 (m, 1H), 1.94-2.04 (m, 3H), 2.17-2.29 (m,1H), 2.71 (q, J=6 Hz, 1H), 2.96-3.03 (m, 1H), 3.08 (t, J=6 Hz, 2H),3.13-3.22 (m, 1H), 3.51-3.59 (m, 1H), 3.66 (t, J=6 Hz, 2H), 7.11 (d, J=9Hz, 2H), 7.30 (d, J=9 Hz, 2H). MS (DCl—NH₃) m/z 285 (M+H)⁺.

Example 411-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]-methyl}cyclopropyl)phenyl]azepan-2-one

The title compound was prepared using the procedure described in Example34G substituting azepan-2-one for pyridazin-3(2H)-one, ¹H NMR (300 MHz,CD₃OD) δ 0.98-1.05 (m, 1H), 1.09-1.16 (m, 1H), 1.32 (d, J=6 Hz, 3H),1.36-1.39 (m, 1H), 1.59-1.69 (m, 1H), 1.83 (broad, 6H), 1.94-2.0 (m,3H), 2.16-2.27 (m, 1H), 2.61-2.71 (m, 2H), 2.90-2.98 (m, 1H), 3.07-3.14(m, 1H), 3.32-3.37 (m, 1H), 3.48-3.58 (m, 1H), 3.75-3.78 (m, 1H), 7.13(d, J=3 Hz, 4H). MS (DCl—NH₃) m/z 327 (M+H)⁺.

Example 421-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]piperidin-2-one

The title compound was prepared using the procedure described in Example34G substituting piperidin-2-one for pyridazin-3(2H)-one. ¹H NMR (300MHz, CD₃OD) δ 0.97-1.03 (m, 1H), 1.08-1.15 (m, 1H), 1.30 (d, J=6 Hz,3H), 1.31-1.38 (m, 1H), 1.56-1.63 (m, 1H), 1.92-1.99 (m, 3H), 2.14-2.24(m, 3H), 2.49 (t, J=6 Hz, 2H), 2.52-2.59 (m, 1H), 2.81-2.90 (m, 1H),2.96-3.04 (m, 1H), 3.44-3.54 (m, 1H), 3.61-3.65 (m, 2H), 7.17 (d, J=3Hz, 4H) MS (DCl—NH₃) m/z 313 (M+H)⁺.

Example 431-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrrolidin-2-one

The title compound was prepared using the procedure described in Example34G substituting pyrrolidin-2-one for pyridazin-3(2H)-one. ¹H NMR (300MHz, CD₃OD) δ 0.99-1.05 (m, 1H), 1.10-1.16 (m, 1H), 1.34 (d, J=6 Hz,3H), 1.35-1.40 (m, 1H), 1.59-1.71 (m, 1H), 1.95-2.04 (m, 3H), 2.12-2.27(m, 3H), 2.58 (t, J=6 Hz, 2H), 2.67-2.76 (m, 1H), 3.02 (q, J=6 Hz, 1H),3.15-3.22 (m, 1H), 3.31-3.37 (m, 1H), 3.51-3.59 (m, 1H), 3.89 (t, J=6Hz, 2H), 7.13 (d, J=9 Hz, 2H), 7.49 (d, J=9 Hz, 2H). MS (DCl—NH₃) m/z299 (M+H)⁺.

Example 44N-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]acetamide

The title compound was prepared using the procedure described in Example34G substituting acetamide for pyridazin-3(2H)-one, ¹H NMR (300 MHz,CD₃OD) δ 0.98-1.04 (m, 1H), 1.09-1.16 (m, 1H), 1.36 (d, J=6 Hz, 3H),1.29-1.40 (m, 1H), 1.61-1.74 (m, 1H), 1.94-2.06 (m, 3H), 2.10 (s, 3H),2.20-2.32 (m, 1H), 2.77-2.84 (m, 1H), 3.04-3.14 (m, 1H), 3.21-3.27 (m,1H), 3.33-3.39 (m, 1H), 3.55-3.63 (m, 1H), 7.06 (d, J=9 Hz, 2H), 7.44(d, J=9 Hz, 2H). MS (DCl—NH₃) m/z 273 (M+H)⁺.

Determination of Biological Activity

To determine the effectiveness of representative compounds of thisinvention as histamine-3 receptor ligands (H₃ receptor ligands), thefollowing tests were conducted according to methods previously described(European Journal of Pharmacology, 188:219-227 (1990); Journal ofPharmacology and Experimental Therapeutics, 275:598-604 (1995), Journalof Pharmacology and Experimental Therapeutics, 276:1009-1015 (1996), andBiochemical Pharmacology, 22:3099-3108 (1973)).

Briefly, male Sprague-Dawley rat brain cortices were homogenized (1 gtissue/b mL buffer) in 50 mM Tris-HCl/5 mM EDTA containing proteaseinhibitor cocktail (Calbiochem) using a polytron set at 20,500 rpmHomogenates were centrifuged for 20 minutes at 40,000×g. The supernatantwas decanted, and pellets were weighed. The pellet was resuspended bypolytron homogenization in 40 mL 50 mM Tris-HCl/5 mM EDTA with proteaseinhibitors and centrifuged for 20 minutes at 40,000×g. The membranepellet was resuspended in 6.25 volumes (per gram wet weight of pellet)of 50 mM Tris-HCl/5 mM EDTA with protease inhibitors and aliquots flashfrozen in liquid N₂ and stored at −70° C. until used in assays. Ratcortical membranes (12 mg wet weight/tube) were incubated with(³H)—N-α-methylhistamine (˜0.6 nM) with or without H₃ receptorantagonists in a total incubation volume of 0.5 mL of 50 mM Tris-HCl/5mM EDTA (pH 7.7). Test compounds were dissolved in DMSO to provide a 20mM solution, serially diluted and then added to the incubation mixturesprior to initiating the incubation assay by addition of the membranes.Thioperamide (3 μM) was used to determine nonspecific binding, Bindingincubations were conducted for 30 minutes at 25° C. and terminated byaddition of 2 mL of ice cold 50 mM Tris-HCl (pH 7.7) and filtrationthrough 0.3% polyethylenimine-soaked Unifilter plates (Packard). Thesefilters were washed 4 additional times with 2 mL of ice-cold 50 mMTris-HCl and dried for 1 hour. Radioactivity was determined using liquidscintillation counting techniques. Results were analyzed by Hilltransformation and K_(i) values were determined using the Cheng-Prusoffequation.

As an alternative to the use of cortical membranes from rats as a sourceof histamine H₃ receptors, membranes prepared from cells expressing H₃receptors are also suitable. For this, the rat histamine H₃ receptor,cloned and expressed in cells was used, and subsequently competitionbinding assays were carried out according to methods previouslydescribed (see Esbenshade, et al. Journal of Pharmacology andExperimental Therapeutics, vol. 313.165-175, 2005; Esbenshade et al.,Biochemical Pharmacology vol. 68 (2004) 933-945; Krueger, et al. Journalof Pharmacology and Experimental Therapeutics, vol. 314:271-281, 2005.)Membranes were prepared from C6 or HEK293 cells, expressing the rathistamine H₃ receptor, by homogenization on ice in TE buffer (50 mMTris-HCl buffer, pH 74, containing 5 mM EDTA), 1 mM benzamidine, 2 μg/mlaprotinin, 1 μg/ml leupeptin, and 1 μg/ml pepstatin. The homogenate wascentrifuged at 40,000 g for 20 minutes at 4° C. This step was repeated,and the resulting pellet was resuspended in TE buffer Aliquots werefrozen at −70° C. until needed. On the day of assay, membranes werethawed and diluted with TE buffer.

Membrane preparations were incubated with [³H]-N-α-methylhistamine(0.5-1.0 nM) in the presence or absence of increasing concentrations ofligands for H₃ receptor competition binding. The binding incubationswere conducted in a final volume of 0.5 ml TE buffer at 25° C. and wereterminated after 30 minutes. Thioperamide (30 μM) was used to definenon-specific binding. All binding reactions were terminated byfiltration under vacuum onto polyethylenimine (0.3%) presoakedUnifilters (Perkin Elmer Life Sciences) or Whatman GF/B filters followedby three brief washes with 2 ml of ice-cold TE buffer. Bound radiolabelwas determined by liquid scintillation counting. For all of theradioligand competition binding assays, IC₅₀ values and Hill slopes weredetermined by Hill transformation of the data and pK_(i) values weredetermined by the Cheng-Prusoff equation.

Generally, representative compounds of the invention demonstratedbinding affinities in the above assays from about 0.05 nM to about 1000nM. Preferred compounds of the invention bound to histamine-3 receptorswith binding affinities from about 0.05 nM to about 250 nM Morepreferred compounds of the invention bound to histamine-3 receptors withbinding affinities from about 0.05 nM to about 10 nM.

In addition to the utility of in vitro methods for characterizing the H₃binding affinity of compounds, there are animal models of human diseaseavailable which demonstrate the utility of compounds of the inventionfor treating human disease.

One animal model of the human disease ADHD (attention deficithyperactivity disorder) and related human disorders of attention is aninhibitory avoidance test in SHR rat pups (a Spontaneously Hypertensivestrain of rat pups). This model has also been alternatively termed a PAR(passive avoidance response) model. The methodology and utility of thistest has been described in the literature, for example in Komater, V.A., et al. Psychopharmacology (Berlin, Germany) (2003), 167(4), 363-372,in “Two novel and selective nonimidazole H₃ receptor antagonistsA-304121 and A-317920: II. In vivo behavioral and neurophysiologicalcharacterization.” Fox, G. B., et al. Journal of Pharmacology andExperimental Therapeutics (2003), 305(3), 897-908, in Cowart, et al. J.Med. Chem. 2005, 48, 38-55, in Fox, G. B., et al. “PharmacologicalProperties of ABT-239: II. Neurophysiological Characterization and BroadPreclinical Efficacy in Cognition and Schizophrenia of a Potent andSelective Histamine H₃ Receptor Antagonist”, Journal of Pharmacology andExperimental Therapeutics (2005) 313, 176-190; in “Effects of histamineH₃ receptor ligands GT-2331 and ciproxifan in a repeated acquisitionavoidance response in the spontaneously hypertensive rat pup.” Fox, G.B., et al. Behavioural Brain Research (2002), 131(1,2), 151-161.Representative compounds are active in this model, with preferredcompounds of the invention active in the model at doses of ranging about0.001-3 mg/kg of body weight.

Compounds of the invention are histamine-3 receptor ligands thatmodulate the function of the histamine-3 receptor. The compounds may beinverse agonists that inhibit the basal activity of the receptor or theymay be antagonists that block the action of receptor-activatingagonists.

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations, or methods, or anycombination of such changes and modifications of use of the invention,may be made without departing from the spirit and scope thereof.

What is claimed is:
 1. A compound of formula:

or a pharmaceutically acceptable salt, ester, or amide thereof, wherein: one of R₁ and R₂ is a group of the formula -L₂-R_(6a)-L₃-R_(6b); the other of R₁ and R₂ is selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, cyano, and thioalkoxy, R₃, R_(3a), and R_(3b) are each independently selected from the group consisting of hydrogen, alkyl, trifluoroalkyl, trifluoroalkoxy, alkoxy, halogen, cyano, and thioalkoxy; R₄ and R₅ taken together with the nitrogen atom to which each is attached form a non-aromatic ring of the formula:

R₇, R₈, R₉, and R₁₀ at each occurrence are each independently selected from the group consisting of hydrogen, hydroxyalkyl, fluoroalkyl, cycloalkyl, and alkyl; R₁₁, R₁₂, R₁₃, and R₁₄ are each independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, and fluoroalkyl; R_(6a) is a cyanophenyl or an unsubstituted or substituted ring selected from the group consisting of furyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, [1,2,3]thiadiazolyl, [1,2,3]oxadiazolyl, thiazolyl, thienyl, [1,2,3]triazinyl, [1,2,4]triazinyl, [1,3,5]triazinyl, [1,2,3]triazolyl, [1,2,4]triazolyl, azepanyl, azetidinyl, aziridinyl, azocanyl, dihydropyridazinyl, dihydropyridinyl, dihydropyrimidinyl, morpholinyl, pyrrolinyl, dihydrothiazolyl, dihydropyridinyl, thiomorpholinyl, dioxanyl, dithianyl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, [1,3]dioxolanyl, azetidin-2-onyl, azepan-2-onyl, isoindolin-1,3-dionyl, (Z)-1H-benzo[e][1,4]diazepin-5(4H)-onyl, pyridazin-3(2H)-onyl, pyridin-2(1H)-onyl, pyrimidin-2(1H)-onyl, pyrimidin-2,4(1H,3H)-dionyl, pyrrolidin-2-onyl, benzo [dl thiazol-2(3H)-onyl, pyridin-4(1H)-onyl, imidazolidin-2-onyl, 1H-imidazol-2(3H)onyl, tetrahydropyrimidin-2(1H)-onyl, [1,2,4]thiadiazolonyl, [1,2,5]thiadiazolonyl, [1,3,4]thiadiazinonyl, [1,2,4]oxadiazolonyl, [1,2,5]oxadiazolonyl, [1,3,4]oxadiazin-onyl, and 1H-benzo[d]imidazol-2(3H)-onyl; R_(6b) is hydrogen; Q is O or S; L is —[C(R₁₆)(R₁₇)]_(k); L₂ is selected from the group consisting of a bond, alkylene, —O—, —C(═O)—, —S—, —NH—, —N(R₁₆)C(═O)—, —C(═O)N(R₁₆), and —N(alkyl)-; L₃ is a bond; R₁₅ is selected from the group consisting of hydrogen, alkyl, acyl, alkoxycarbonyl, amido, and formyl; R₁₆ and R₁₇ at each occurrence are independently selected from the group consisting of hydrogen and alkyl; R_(x) and R_(y) at each occurrence are independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, alkyl, alkoxy, alkylamino, fluoro, and dialkylamino; k is 1, 2 or 3; and m is
 2. 2. The compound of claim 1, wherein R₄ and R₅ are taken together with the nitrogen atom to which each is attached to form a (2R)-methylpyrrolidine ring or (2S)-methylpyrrolidine ring.
 3. The compound of claim 1, wherein the compound has the formula


4. The compound of claim 1, wherein the compound has the formula


5. The compound of claim 1, wherein R₁ is -L₂-R_(6a)-L₃-R_(6b) and R_(6a) is pyridazin-3(2H)-onyl.
 6. The compound of claim 1, selected from the group consisting of 4′-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrile; 4′-((1S,2S)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrile; 4′-((1R_(,)2R)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrile; 4′-((1R,2R)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrile; 4′-{(1S,2S)-2-[(2-methylpyrrolidin-1-yl)methyl]cyclopropyl}-1,1′-biphenyl-4-carbonitrile; 5-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidine; 2-methoxy-5-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidine; 2,6-dimethyl-3-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridine; 2-methoxy-5-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridine; 5-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidine; 5-[4-((1R,2R)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidine; 5-[4-((1R,2R)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidine; 2,4-dimethoxy-5-[4-((1R,2R)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidine; 2,4-dimethoxy-5-[4-((1R,2R)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidine; 2,4-dimethoxy-5-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidine; 2,4-dimethoxy-5-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidine; 2-[4-((1R,2R)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-one; 2-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-one; 1,3,5-trimethyl-4-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]-1H-pyrazole; 2,6-dimethyl-3-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridine; N-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidin-5-amine; 4′-((1R,2S)-2-{2-[(2R)-2-methylpyrrolidin-1-yl]ethyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrile; 4′-((1S,2R)-2-{2-[(2R)-2-methylpyrrolidin-1-yl]ethyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrile; 4′-[(trans)-2-(2-pyrrolidin-1-ylethyl)cyclopropyl]-1,1′-biphenyl-4-carbonitrile; N-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]isonicotinamide; 2-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-one; 1-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]azepan-2-one; 1-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]azetidin-2-one; 1-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]azetidin-2-one; 1-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]azepan-2-one; N-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]-1H-1,2,4-triazole-3-carboxamide; 4′-{(1S,2R)-2-[2-(2-methylpyrrolidin-1-yl)ethyl]cyclopropyl}-1,1′-biphenyl-4-carbonitrile; 4′-((1S,2R)-2-{2-[(3R)-3-hydroxypyrrolidin-1-yl]ethyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrile; and 4′-((1S,2R)-2-{2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]ethyl}cyclopropyl)-1,1′-biphenyl-4-carbonitrile.
 7. A compound selected from the group consisting of 2-methoxy-5-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidine; 2-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-one; and 2-[4-((1S,2S)-{2-[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-one, or a salt thereof.
 8. A compound that is 2-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-one or a salt thereof.
 9. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable carrier.
 10. A compound that is 2-methoxy-5-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyrimidine or a salt thereof.
 11. A compound that is 2-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-one or a salt thereof.
 12. The compound of claim 1, wherein R_(6a) is an unsubstituted ring selected from the group consisting of furyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, [1,2,3]thiadiazolyl, [1,2,3]oxadiazolyl, thiazolyl, thienyl, [1,2,3]triazinyl, [1,2,4]triazinyl, [1,3,5]triazinyl, [1,2,3]triazolyl, [1,2,4]triazolyl, azepanyl, azetidinyl, aziridinyl, azocanyl, dihydropyridazinyl, dihydropyridinyl, dihydropyrimidinyl, morpholinyl, pyrrolinyl, dihydrothiazolyl, dihydropyridinyl, thiomorpholinyl, dioxanyl, dithianyl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, [1,3]dioxolanyl, azetidin-2-onyl, azepan-2-onyl, isoindolin-1,3-dionyl, (Z)-1H-benzo[e][1,4]diazepin-5(4H)-onyl, pyridazin-3(2H)-onyl, pyridin-2(1H)-onyl, pyrimidin-2(1H)onyl, pyrimidin-2,4(1H,3H)-dionyl, pyrrolidin-2-onyl, benzo[d]thiazol-2(3H)-onyl, pyridin-4(1H)-onyl, imidazolidin-2-onyl, 1 H-imidazol-2(3H)-onyl, tetrahydropyrimidin-2(1H)-onyl, [1,2,4]thiadiazolonyl, [1,2,5]thiadiazolonyl, [1,3,4]thiadiazinonyl, [1,2,4]oxadiazolonyl, [1,2,5]oxadiazolonyl, [1,3,4]oxadiazin-onyl, and 1H-benzo[d]imidazol-2(3H)-onyl.
 13. The compound of claim 1, wherein R_(6a) is a substituted ring selected from the group consisting of furyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, [1,2,3]thiadiazolyl, [1,2,3]oxadiazolyl, thiazolyl, thienyl, [1,2,3]triazinyl, [1,2,4]triazinyl, [1,3,5]triazinyl, [1,2,3]triazolyl, [1,2,4]triazolyl, azepanyl, azetidinyl, aziridinyl, azocanyl, dihydropyridazinyl, dihydropyridinyl, dihydropyrimidinyl, morpholinyl, pyrrolinyl, dihydrothiazolyl, dihydropyridinyl, thiomorpholinyl, dioxanyl, dithianyl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, [1,3]dioxolanyl, azetidin-2-onyl, azepan-2-onyl, isoindolin-1,3-dionyl, (Z)-1H-benzo[e][1,4]diazepin-5(4H)-onyl, pyridazin-3(2H)-onyl, pyridin-2(1H)-onyl, pyrimidin-2(1H)onyl, pyrimidin-2,4(1H,3H)-dionyl, pyrrolidin-2-onyl, benzo[d]thiazol-2(3H)-onyl, pyridin-4(1H)-onyl, imidazolidin-2-onyl, 1H-imidazol-2(3H)-onyl, tetrahydropyrimidin-2(1H)-onyl, [1,2,4]thiadiazolonyl, [1,2,5]thiadiazolonyl, [1,3,4]thiadiazinonyl, [1,2,4]oxadiazolonyl, [1,2,5]oxadiazolonyl, [1,3,4]oxadiazin-onyl, and 1H-benzo[d]imidazol-2(3H)-onyl.
 14. The compound of claim 13, wherein the substituted ring is substituted with a substituent selected from the group consisting of acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl, amido, carboxy, cyano, cycloalkyl, fluoroalkoxy, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, alkylthio, —NR_(A)R_(B), and (NR_(A)R_(B))carbonyl.
 15. The compound of claim 13, wherein the substituted ring is substituted with 1, 2, 3, 4, or 5 substituents. 